recent advances in synthesis & chemical biology ix · recent advances in synthesis &...

Recent Advances in Synthesis& Chemical Biology IX___________________________

Symposium10th December 2010

Davenport Hotelat Merrion Square,Dublin 2

‘Recent Advances in Synthesis and Chemical Biology IX’10th December 2010

The Centre for Synthesis and Chemical Biology wishes to thankthe following sponsors for their support for this symposium:

Centre for Synthesis & Chemical

“Recent Advances in Synthesis and Chemical Biology IX”

Davenport Hotel, at Merrion Square, Dublin 2, Ireland

08.50am-9.00am Opening sessionDr. David Lloyd, Dean of Research, Trinity College DublinProfessor Mathias Senge, Trinity College Dublin

9.00am-09.45am Chairperson: Professor Marek Radomski, Trinity College DublinDRHEA LectureProfessor Itamar Willner,Israel‘Sensing with Nanoparticles, Quantum Dots and Biomolecular Nanostructures

09.45am-10.30am Chairperson: Professor Kevin Nolan, Royal College of Surgeons IrelandDRHEA LectureDr. Anne‘Biochemical Approaches to Biomolecular Networks

10.30am-11.00am Coffee/Tea Break

11.00am-11.45am Chairperson: Dr. Wolfgang Schmitt, Trinity College DublinDRHEA LectureProf. Pierre Braunstein, Université Louis Pasteur, Strasbourg, France‘The Chemistry of Heterofunctional Ligands: from Homogeneous Catalysts to 1Bimetallic Wires and Clusters

11.45am-12.30pm Chairperson: Dr. Cormac Murphy, University College DublinInstitut de Recherches ServierProfessor David O'Hagan,‘The stereoelectronic influence of the C

12.30pm-1.45pm Lunch Break

1.45pm-2.30pm Chairperson: Professor Pat Guiry, University College DublinGlaxoSmithKline LectureProfessor Reinhard Brückner, Universität Freiburg, Freiburg, Germany‘Evolution of a Synthetic Strategy Towards the Unnatural Enantiomer of thePolyol/Polyene Antibiotic Nystatin AChemoselective

2.30pm-4.00pm Poster Session. Coffee/Tea Break

4.00pm-4.45pm Chairperson:Eli Lilly LectureProfessor Bernhard Kräutler, Universität'News on an Old Puzzle

4.45pm-5.00pm Closing RemarksProfessor Pat Guiry, Director, Centre for Synthesis and Chemical Biology

5.00pm-6.00pm Wine Reception in the Restaurant, 1

Centre for Synthesis & ChemicalBiology

“Recent Advances in Synthesis and Chemical Biology IX”Friday, 10th December, 2010


PRELIMINARY PROGRAMME

Opening sessionDr. David Lloyd, Dean of Research, Trinity College DublinProfessor Mathias Senge, Trinity College Dublin

Chairperson: Professor Marek Radomski, Trinity College DublinDRHEA LectureProfessor Itamar Willner, The Hebrew University of JIsraelSensing with Nanoparticles, Quantum Dots and Biomolecular Nanostructures

Chairperson: Professor Kevin Nolan, Royal College of Surgeons IrelandDRHEA LectureDr. Anne-Claude Gavin, EMBL, Heidelberg, GermanyBiochemical Approaches to Biomolecular Networks’

Coffee/Tea Break

Chairperson: Dr. Wolfgang Schmitt, Trinity College DublinDRHEA LectureProf. Pierre Braunstein, Université Louis Pasteur, Strasbourg, FranceThe Chemistry of Heterofunctional Ligands: from Homogeneous Catalysts to 1Bimetallic Wires and Clusters’

Chairperson: Dr. Cormac Murphy, University College DublinInstitut de Recherches Servier LectureProfessor David O'Hagan, University of St. Andrews, St. Andrews, UKThe stereoelectronic influence of the C-F bond for design in organic chemistry

Lunch Break

Chairperson: Professor Pat Guiry, University College DublinGlaxoSmithKline LectureProfessor Reinhard Brückner, Universität Freiburg, Freiburg, GermanyEvolution of a Synthetic Strategy Towards the Unnatural Enantiomer of thePolyol/Polyene Antibiotic Nystatin A1 - The -Lactone Approach to 1,3Chemoselective Hydrogenations of -Ketocarboxylic Acid Derivatives

Poster Session. Coffee/Tea Break

Chairperson: Professor Thorfinnur Gunnlaugsson, Trinity College DublinEli Lilly LectureProfessor Bernhard Kräutler, Universität Innsbruck, Innsbruck, Austria'News on an Old Puzzle - Chlorophyll Breakdown in Leaves and Fruit'

Closing RemarksProfessor Pat Guiry, Director, Centre for Synthesis and Chemical Biology

Wine Reception in the Restaurant, 1st Floor, Davenport

Investing in your future

“Recent Advances in Synthesis and Chemical Biology IX”


Chairperson: Professor Marek Radomski, Trinity College Dublin

The Hebrew University of Jerusalem, Jerusalem,

Sensing with Nanoparticles, Quantum Dots and Biomolecular Nanostructures’

Chairperson: Professor Kevin Nolan, Royal College of Surgeons Ireland

Prof. Pierre Braunstein, Université Louis Pasteur, Strasbourg, FranceThe Chemistry of Heterofunctional Ligands: from Homogeneous Catalysts to 1-D

Chairperson: Dr. Cormac Murphy, University College Dublin

University of St. Andrews, St. Andrews, UKF bond for design in organic chemistry’

Chairperson: Professor Pat Guiry, University College Dublin

Professor Reinhard Brückner, Universität Freiburg, Freiburg, GermanyEvolution of a Synthetic Strategy Towards the Unnatural Enantiomer of the

Lactone Approach to 1,3-Diols andKetocarboxylic Acid Derivatives’

Professor Thorfinnur Gunnlaugsson, Trinity College Dublin

Innsbruck, Innsbruck, AustriaChlorophyll Breakdown in Leaves and Fruit'

Professor Pat Guiry, Director, Centre for Synthesis and Chemical Biology


Invited Speakers:

Profiles

Professor Itamar Willner, The Hebrew University of Jerusalem, Jerusalem,Israel

Itamar Willner obtained his PhD in 1978 in Physical Organic Chemistry. Hemoved on the U.C. Berkeley where he studied as a post1980) and served as Staff Scientist and Adjunct Association Professor (19801981). He was appointed as a Lecturer in the(1981) and later became a Professor in the same University (1986).

He has co-authored over 580 publications and over 30 patents. His researchactivities include Supramolecular chemistry, Nanotechnology,Nanobiotechnology and Molecular selfawards and honours including the Bergmann award (1986), the Kolthoff Award(1993), the Kaye Innovations Award (1998 and 2004), the Israeli prize inChemistry (2002) and the EMET prize in chemistry (underPrime Minister of Israel) - 2008.

He served as an Honorary Professor in Osaka University (1991) in TsinghunaUniversity Beijing, China (2005), in the East China University of Science andTechnology, Shanghai, China (2007). He was electAcademy of Science (2002), a member of the European Academy of Scienceand Arts (2004), a fellow of the Royal Society of Chemistry (FRSC) (U.K.)(2009) and a member of the German National Academy of Sciences Leopoldina(2009)

Dr Anne-Claude Gavin, EMBL, Heidelberg, Germany

Anne-Claude Gavin obtained her PhD in the University of Geneva, Switzerlandin 1992. She conducted her postBiology Laboratory (EMBL) in Heidelberg and became a director of Molecularand Cell Biology, Cellzome AGat EMBL since 2005.

She has co-authored over 35 publications, with the most recent beingVisualizing biological data -data for systems biology. She received the Genome Technology AllMost Prolific in Proteomics in 2002 for her work on the "Functional organizationof the yeast proteome by systematic analysis of protein complexes".

EMBL, one of the world's top research institutions, ismonies from 20 member statesFrance, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, theNetherlands, Norway, Portugal, Spain, Sweden, Switzerland, The UnitedKingdom and an associate member state, Australia.

The cornerstones of EMBL's mission are: to perform basic research in molecularbiology, to train scientists, students and visitors at all levels, to offer vitalservices to scientists in the member states, and to devmethods in the life sciences, and technology transfer.

Professor Itamar Willner, The Hebrew University of Jerusalem, Jerusalem,

obtained his PhD in 1978 in Physical Organic Chemistry. Hemoved on the U.C. Berkeley where he studied as a post-doctoral fellow (19781980) and served as Staff Scientist and Adjunct Association Professor (19801981). He was appointed as a Lecturer in the Hebrew University in Jerusalem(1981) and later became a Professor in the same University (1986).

authored over 580 publications and over 30 patents. His researchactivities include Supramolecular chemistry, Nanotechnology,

d Molecular self-assembly. He has received numerousawards and honours including the Bergmann award (1986), the Kolthoff Award(1993), the Kaye Innovations Award (1998 and 2004), the Israeli prize inChemistry (2002) and the EMET prize in chemistry (under the auspices of the

2008.

Professor in Osaka University (1991) in TsinghunaUniversity Beijing, China (2005), in the East China University of Science andTechnology, Shanghai, China (2007). He was elected a member of the IsraeliAcademy of Science (2002), a member of the European Academy of Scienceand Arts (2004), a fellow of the Royal Society of Chemistry (FRSC) (U.K.)(2009) and a member of the German National Academy of Sciences Leopoldina

Claude Gavin, EMBL, Heidelberg, Germany

Claude Gavin obtained her PhD in the University of Geneva, Switzerlandin 1992. She conducted her post-doctoral research in the European Molecular

(EMBL) in Heidelberg and became a director of Molecularand Cell Biology, Cellzome AG in Heidelberg. She has served as a group leader

authored over 35 publications, with the most recent beingnow and in the future and Visualization of omics

She received the Genome Technology All-Stars AwardMost Prolific in Proteomics in 2002 for her work on the "Functional organizationof the yeast proteome by systematic analysis of protein complexes".

EMBL, one of the world's top research institutions, is funded by public researchmonies from 20 member states - Austria, Belgium, Croatia, Denmark, Finland,France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, theNetherlands, Norway, Portugal, Spain, Sweden, Switzerland, The United

d an associate member state, Australia.

The cornerstones of EMBL's mission are: to perform basic research in molecularbiology, to train scientists, students and visitors at all levels, to offer vitalservices to scientists in the member states, and to develop new instruments andmethods in the life sciences, and technology transfer.

Professor Itamar Willner, The Hebrew University of Jerusalem, Jerusalem,

obtained his PhD in 1978 in Physical Organic Chemistry. Hedoctoral fellow (1978-

1980) and served as Staff Scientist and Adjunct Association Professor (1980-Hebrew University in Jerusalem

authored over 580 publications and over 30 patents. His researchactivities include Supramolecular chemistry, Nanotechnology,

assembly. He has received numerousawards and honours including the Bergmann award (1986), the Kolthoff Award(1993), the Kaye Innovations Award (1998 and 2004), the Israeli prize in

the auspices of the

Professor in Osaka University (1991) in TsinghunaUniversity Beijing, China (2005), in the East China University of Science and

ed a member of the IsraeliAcademy of Science (2002), a member of the European Academy of Scienceand Arts (2004), a fellow of the Royal Society of Chemistry (FRSC) (U.K.)(2009) and a member of the German National Academy of Sciences Leopoldina

ProfessorItamar Willner,The HebrewUniversity ofJerusalem,Jerusalem,Israel

Claude Gavin obtained her PhD in the University of Geneva, SwitzerlandEuropean Molecular

(EMBL) in Heidelberg and became a director of Molecularin Heidelberg. She has served as a group leader

authored over 35 publications, with the most recent beingVisualization of omics

Stars AwardMost Prolific in Proteomics in 2002 for her work on the "Functional organization

funded by public researchAustria, Belgium, Croatia, Denmark, Finland,

France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, theNetherlands, Norway, Portugal, Spain, Sweden, Switzerland, The United

The cornerstones of EMBL's mission are: to perform basic research in molecularbiology, to train scientists, students and visitors at all levels, to offer vital

elop new instruments and

Dr AnneClaude Gavin,EMBL,Heidelberg,Germany

Professor Pierre Braunstein, Universite Louis Pasteur, Strasbourg, France

Pierre Braunstein graduated from thein 1969. He obtained his PhD with Jean Dehand in University Louis Pasteur,Strasbourg in 1971. From Nov 1971Research Fellowship with R.S. Nyholm and R.J.H. Clarke in the DepartmenChemistry, University College London, U.K. In 1974 he did a State Doctorate inUniversity Louis Pasteur, Strasbourg. From November 1974studied as a Humboldt Fellow with E.O. Fischer, in AnorganishLaboratorium der Technischen Universität, Munich (Germany).

He is currently Director of Research with the CNRS and the Director of theCoordination Chemistry Laboratory (Institute of Chemistry, UMR 7177 CNRS) ofthe newly reunited “Université de Strasbourg”. His main researchconcern the inorganic and organometallic chemistry of the transition and maingroup elements where he has (co)authored over 400 scientific publications andreview articles.

He is member of various academies including the French Academy of Scienthe German Academy of Sciences Lepoldina, Academia Europaea, theEuropean Academy of Sciences and aUK. He has received numerous national and international awards including OttoWarburg Award Germany (2002),Medal and Lecture UK (2003), Honorary Professor Chinese Academy ofSciences, Institute of Chemistry, Beijing (2006),Academy of Sciences, Institute of Chemistry, Beijing (2006)Huygens Prize, Royal Netherlands Academy of Arts and Sciences and FrenchAcademy of Sciences (2008).

Professor David O’Hagan, University of St. Andrews, St.

David O’Hagan was born in Glasgow and studied chemistry at the University ofGlasgow (1982). He carried out a PhD (1985) in polyketidebiosynthesis at the University of Southampton with Professor John A. Robinsonand then he spent a post-Professor Heinz G Floss, investigating peptide antibiotic biosynthesis. In 1986he was appointed to the University of Durham where he continued to explorenatural product biosynthesis but also developed a strong interest in organofluorine chemistry. He remained at Durham until 2000 before moving to hiscurrent position as Professor and Head of OrSt Andrews.

His research interests extend from the synthesis and properties of organofluorine compounds, fluorination enzymology,emission tomography (PET) and through to fluorinated organiwas a founding member and a recent past Chair of the RSC Fluorine Group andis one of the Vice-Presidents of the RSC Organic Chemistry Executive. He waselected FRSE in 2004, was awarded the RSC Malcolm Campbell MemorialPrize in Medicinal Chemistry in 2005 and was a recipient of the RSC TildenMedal in 2006/2007.


Pierre Braunstein graduated from the Ecole Supérieure de Chimie de Mulhousein 1969. He obtained his PhD with Jean Dehand in University Louis Pasteur,Strasbourg in 1971. From Nov 1971 – Oct 1972 he completed his HonoraryResearch Fellowship with R.S. Nyholm and R.J.H. Clarke in the Department ofChemistry, University College London, U.K. In 1974 he did a State Doctorate inUniversity Louis Pasteur, Strasbourg. From November 1974 – October 1975 hestudied as a Humboldt Fellow with E.O. Fischer, in Anorganish – Chemisches

ischen Universität, Munich (Germany).

He is currently Director of Research with the CNRS and the Director of theCoordination Chemistry Laboratory (Institute of Chemistry, UMR 7177 CNRS) ofthe newly reunited “Université de Strasbourg”. His main research interestsconcern the inorganic and organometallic chemistry of the transition and maingroup elements where he has (co)authored over 400 scientific publications and

He is member of various academies including the French Academy of Sciences,the German Academy of Sciences Lepoldina, Academia Europaea, theEuropean Academy of Sciences and a Fellow of the Royal Society of Chemistry,

has received numerous national and international awards including OttoWarburg Award Germany (2002), Chini Memorial Lecture, Italy (2003), NyholmMedal and Lecture UK (2003), Honorary Professor Chinese Academy ofSciences, Institute of Chemistry, Beijing (2006), Honorary Professor, ChineseAcademy of Sciences, Institute of Chemistry, Beijing (2006) and DescartesHuygens Prize, Royal Netherlands Academy of Arts and Sciences and FrenchAcademy of Sciences (2008).

Professor David O’Hagan, University of St. Andrews, St. Andrews, UK

David O’Hagan was born in Glasgow and studied chemistry at the University ofGlasgow (1982). He carried out a PhD (1985) in polyketide antibioticbiosynthesis at the University of Southampton with Professor John A. Robinson

doctoral year at the Ohio State University withProfessor Heinz G Floss, investigating peptide antibiotic biosynthesis. In 1986

ted to the University of Durham where he continued to explorenatural product biosynthesis but also developed a strong interest in organofluorine chemistry. He remained at Durham until 2000 before moving to hiscurrent position as Professor and Head of Organic Chemistry at the University of

His research interests extend from the synthesis and properties of organofluorine compounds, fluorination enzymology, 18F chemistry for positronemission tomography (PET) and through to fluorinated organic materials. Hewas a founding member and a recent past Chair of the RSC Fluorine Group and

Presidents of the RSC Organic Chemistry Executive. He waselected FRSE in 2004, was awarded the RSC Malcolm Campbell Memorial

Chemistry in 2005 and was a recipient of the RSC Tilden


Ecole Supérieure de Chimie de Mulhousein 1969. He obtained his PhD with Jean Dehand in University Louis Pasteur,

Oct 1972 he completed his Honoraryt of

Chemistry, University College London, U.K. In 1974 he did a State Doctorate inOctober 1975 he

Chemisches

He is currently Director of Research with the CNRS and the Director of theCoordination Chemistry Laboratory (Institute of Chemistry, UMR 7177 CNRS) of

interestsconcern the inorganic and organometallic chemistry of the transition and maingroup elements where he has (co)authored over 400 scientific publications and

ces,the German Academy of Sciences Lepoldina, Academia Europaea, the

Fellow of the Royal Society of Chemistry,has received numerous national and international awards including Otto-

Chini Memorial Lecture, Italy (2003), NyholmMedal and Lecture UK (2003), Honorary Professor Chinese Academy of

Honorary Professor, Chinesescartes –

Huygens Prize, Royal Netherlands Academy of Arts and Sciences and French

ProfessorPierreBraunstein,UniversiteLouis Pasteur,Strasbourg,France

David O’Hagan was born in Glasgow and studied chemistry at the University ofantibiotic

biosynthesis at the University of Southampton with Professor John A. Robinsondoctoral year at the Ohio State University with

Professor Heinz G Floss, investigating peptide antibiotic biosynthesis. In 1986ted to the University of Durham where he continued to explore

natural product biosynthesis but also developed a strong interest in organo-fluorine chemistry. He remained at Durham until 2000 before moving to his

ganic Chemistry at the University of

His research interests extend from the synthesis and properties of organo-F chemistry for positron

c materials. Hewas a founding member and a recent past Chair of the RSC Fluorine Group and

Presidents of the RSC Organic Chemistry Executive. He waselected FRSE in 2004, was awarded the RSC Malcolm Campbell Memorial

Chemistry in 2005 and was a recipient of the RSC Tilden

Professor DavidO’Hagan,University of St.Andrews, St.Andrews, UK

Professor Reinhard Brückner, Universitat Freiburg, Freiburg, Germany

Reinhard Brückner studied Chemistry at the University of Munich from 19741980 and completed his PhD with Professor Dr. R. Huisgen in 1984. From 19841985 he was a post-doctoral fellow with Prof. Paul A. Wender in StanfordUniversity, USA. In 1991 he was appointed Professo3) at the University of Würzburg before moving on to become Professor ofOrganic Chemistry (C-4) in the University of Göttingen in 1992. Since 1998Professor Brückner has been Professor of Organic Chemistry (CUniversity of Freiburg.

He served as a visiting Professor in Autumn 1990 in the University of Wisconsin,Madison, USA, in spring 1995 in Universidade de Santiago de Compostela,Spain and in Autumn/Winter 2003/2004 in Indiana University, Bloomington,USA.

Brϋckner has won many awards including the ADUCpostdoctoral (1989), the Karl Winnacker Fellowship (1990), the ChemistryAward of the Academy of Sciences and Humanities (1990), the Society ofSynthetic Organic Chemistry, Japan 1996 Lectureship, LiterChemical Industry Fund (1998) and the Novartis Chemistry Lectureship (2008).

His research interests are in the total synthesis of natural products, thesynthesis of biologically active analogues thereof, and development of efficientsynthetic methodology.

Professor Bernhard Kräutler, Universität Innsbruck, Innsbruck, Austria

Bernhard Krautler began his studies in 1966 at the Department of Chemistry,Swiss Federal Institute of Technology (ETH), Zstudies with Professor A. Eschenmoser from 1971 to 1976. In 1977 he studiedas a post-doctoral fellow with Professor ATexas as Fellow of the Swiss National Science Foundation and he followed thisup in 1978 by further post-doctoral research with Professor N.J. Turro, ColumbiaUniversity New York. He joined theEschenmoser at the Laboratory of Organic Chemistry and was Head Assistantfrom 1982-1985. From 1986-1991, he was head of an independent research unitat the Laboratory of Organic Chemistry of the ETH and Lecturer in theDepartments of Chemistry and Biology. InOrganic Chemistry of the University of Innsbruck as Professor of OrganicChemistry. He has been Head of the Institute since 2001.

His awards include a silver medal of the ETH in 1977, Werner Award of theSwiss Chemical Society in 1987, the ErnstAcademy of Sciences in 1996, the Erwin Schrödinger Award of the AustrianAcademy of Sciences in 2001 and in 2005 he won the Joseph Loschmidt Medalof the Austrian Chemical Society.

He is currently a member of the Austrian Academy of Sciences, the EuropeanAcademy of Sciences and the German Academy of Sciences Lepoldina.

His research areas concern the discovery, design, synthesis and analysis ofmolecular units and the investigation oflife and in technology.

ckner, Universitat Freiburg, Freiburg, Germany

studied Chemistry at the University of Munich from 19741980 and completed his PhD with Professor Dr. R. Huisgen in 1984. From 1984

doctoral fellow with Prof. Paul A. Wender in StanfordUniversity, USA. In 1991 he was appointed Professor of Organic Chemistry (C3) at the University of Würzburg before moving on to become Professor of

4) in the University of Göttingen in 1992. Since 1998Professor Brückner has been Professor of Organic Chemistry (C-4) in the

He served as a visiting Professor in Autumn 1990 in the University of Wisconsin,Madison, USA, in spring 1995 in Universidade de Santiago de Compostela,Spain and in Autumn/Winter 2003/2004 in Indiana University, Bloomington,

has won many awards including the ADUC-year award forpostdoctoral (1989), the Karl Winnacker Fellowship (1990), the ChemistryAward of the Academy of Sciences and Humanities (1990), the Society ofSynthetic Organic Chemistry, Japan 1996 Lectureship, Literature Prize of theChemical Industry Fund (1998) and the Novartis Chemistry Lectureship (2008).

His research interests are in the total synthesis of natural products, thesynthesis of biologically active analogues thereof, and development of efficient

Professor Bernhard Kräutler, Universität Innsbruck, Innsbruck, Austria

began his studies in 1966 at the Department of Chemistry,Swiss Federal Institute of Technology (ETH), Zürich. He completed his graduatestudies with Professor A. Eschenmoser from 1971 to 1976. In 1977 he studied

doctoral fellow with Professor A. J. Bard in the University of AustinTexas as Fellow of the Swiss National Science Foundation and he followed this

doctoral research with Professor N.J. Turro, ColumbiaUniversity New York. He joined the ETH in 1979 as Assistant to Prof. A.Eschenmoser at the Laboratory of Organic Chemistry and was Head Assistant

1991, he was head of an independent research unitat the Laboratory of Organic Chemistry of the ETH and Lecturer in the

y and Biology. In 1991 he joined the Institute ofOrganic Chemistry of the University of Innsbruck as Professor of OrganicChemistry. He has been Head of the Institute since 2001.

His awards include a silver medal of the ETH in 1977, Werner Award of theSwiss Chemical Society in 1987, the Ernst-Späth-Award of the AustrianAcademy of Sciences in 1996, the Erwin Schrödinger Award of the AustrianAcademy of Sciences in 2001 and in 2005 he won the Joseph Loschmidt Medalof the Austrian Chemical Society.

is currently a member of the Austrian Academy of Sciences, the EuropeanAcademy of Sciences and the German Academy of Sciences Lepoldina.

His research areas concern the discovery, design, synthesis and analysis ofmolecular units and the investigation of their function and application in natural

studied Chemistry at the University of Munich from 1974-1980 and completed his PhD with Professor Dr. R. Huisgen in 1984. From 1984-

doctoral fellow with Prof. Paul A. Wender in Stanfordr of Organic Chemistry (C-

3) at the University of Würzburg before moving on to become Professor of4) in the University of Göttingen in 1992. Since 1998

4) in the

He served as a visiting Professor in Autumn 1990 in the University of Wisconsin,Madison, USA, in spring 1995 in Universidade de Santiago de Compostela,Spain and in Autumn/Winter 2003/2004 in Indiana University, Bloomington,

year award forpostdoctoral (1989), the Karl Winnacker Fellowship (1990), the ChemistryAward of the Academy of Sciences and Humanities (1990), the Society of

ature Prize of theChemical Industry Fund (1998) and the Novartis Chemistry Lectureship (2008).

synthesis of biologically active analogues thereof, and development of efficient

ProfessorReinhardBrϋckner, UniversitatFreiburg,Freiburg,Germany

rich. He completed his graduatestudies with Professor A. Eschenmoser from 1971 to 1976. In 1977 he studied

Texas as Fellow of the Swiss National Science Foundation and he followed thisdoctoral research with Professor N.J. Turro, Columbia

Eschenmoser at the Laboratory of Organic Chemistry and was Head Assistant1991, he was head of an independent research unit

Academy of Sciences in 2001 and in 2005 he won the Joseph Loschmidt Medal

is currently a member of the Austrian Academy of Sciences, the European

their function and application in natural

ProfessorBernardKräutler,UniversitatInnsbruck,Innsbruck,Austria

PLENARY LECTURES

L1 DRHEA LectureProfessor Itamar Willner, The Hebrew University of Jerusalem,Jerusalem, Israel‘Sensing with Nanoparticles, Quantum Dots and BiomolecularNanostructures’

L2 DRHEA LectureDr. Anne-Claude Gavin, EMBL, Heidelberg, Germany‘Biochemical Approaches to Biomolecular Networks’

L3 DRHEA LectureProf. Pierre Braunstein, Université Louis Pasteur, Strasbourg,France‘The Chemistry of Heterofunctional Ligands: from Homogeneous Catalyststo 1-D Bimetallic Wires and Clusters’

L4 DRHEA LectureProfessor David O'Hagan, University of St. Andrews, St. Andrews,UK‘The stereoelectronic influence of the C-F bond for design in organicchemistry’

L5 GlaxoSmithKline LectureProfessor Reinhard Brückner, Universität Freiburg, Freiburg,Germany‘Evolution of a Synthetic Strategy Towards the Unnatural Enantiomer ofthe Polyol/Polyene Antibiotic Nystatin A1 - The -Lactone Approach to 1,3-Diols and Chemoselective Hydrogenations of -Ketocarboxylic AcidDerivatives’

L6 Eli Lilly LectureProfessor Bernhard Kräutler, Universität Innsbruck, Innsbruck,Austria'News on an Old Puzzle - Chlorophyll Breakdown in Leaves and Fruit'

L1

Sensing with Nanoparticles, Quantum Dots and BiomolecularNanostructures

Itamar WillnerInstitute of Chemistry

The Hebrew University of Jerusalem91904 Jerusalem, Israel

Metal nanoparticles (NPs) and semiconductor quantum dots (QDs) exhibit unique

electronic, optical and catalytic properties. These features enable the application of the NPs

and QDs as functional units for developing new electronic or optical sensors. This area will

be exemplified with the electrical contacting of redox enzymes with electrodes by means of

metal nanoparticles and the assembly of DNA or aptamer-based electrochemical sensors using

Pt NPs as labels. The unique plasmonic properties of metal NPs are used to develop optical

enzyme biosensors, and amplified surface plasmon resonance sensors for the detection of

DNA hybridization or aptamer-substrate complexes. Semiconductor QDs are used for the

development of optical or photoelectrochemical sensor devices using the FRET, electron-

transfer quenching, chemiluminescence or photoelectrochemical mechanisms.

Finally, biomolecular nanostructures, and specifically DNA machines, provide

functional assemblies for amplified sensing. Several isothermal replication molecular DNA

machines will be introduced, and their versatility as new alternatives for the polymerase chain

reaction (PCR) will be discussed.

L2

Biochemical Approaches to Biomolecular Networks

Anne-Claude Gavin

EMBL, Heidelberg, Germany

ABSTRACT

Since the sequencing of the first eukaryotic genome, Saccharomyces cerevisiae, more than 10 years

ago, explosion of new analytical tools in the fields of transcriptomics, proteomics and metabolomics

contributes ever-growing molecular repertoires of the building blocks that make up a cell. Biology

does not rely on biomolecules acting in isolation. Biological function depends on the concerted action

of molecules acting in protein complexes, pathways or networks. Biomolecular interactions are central

to all biological functions. In human, for example, impaired or deregulated protein–protein or protein–

metabolite interaction often leads to disease. Recent strategies have been designed that allow the study

of interactions more globally at the level of entire biological systems. We will discuss the use of these

biochemical approaches to genome-wide screen in model organisms.

L4

The stereoelectronic influence of the C-F bond for design in organic chemistry

David O'HaganSchool of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK

[email protected]

We have been interested in preparing molecules that explore the influence of fluorinein organic chemistry, particulary in terms of conformation. The C-F bond is polar,and the resultant dipole interacts with other functional groups, and other fluorineatoms, in a predictable manner. For example we have prepared singlediastereoisomers of molecules carrying three,1,2 four,3,4 five5 and six6 vicinal fluorinesalong a hydrocarbon chain. These represent new motifs in organo-fluorine chemistry,where the molecules are formally intermediate between hydrocarbon andfluorocarbon entities, and of course stereochemistry is an important design feature.

Other molecules, where the C-F bond interacts with charged groups7,8 to influenceconformation, such as DNA binding ligands, will be highlighted.

References1) M. Nicoletti, D. O’Hagan, A M Z Slawin, J. Am. Chem. Soc., 2005, 127, 482-483.2) S. Bresciani, T. Lebl, A. M. Z. Slawin, D. O’Hagan, Chem. Commun, 2010, 5434 – 5436.3) L. Hunter, A. M. Z. Slawin, P. Kirsch, D. O’Hagan Angew. Chemie Int. Ed., 2007, 46, 7887 - 7890.4) L. Hunter, D. O’Hagan, A. M. Z. Slawin, J. Am. Chem. Soc., 2006, 128, 16422 – 16423.5) D. Farran, A. M. Z. Slawin, P. Kirsch, D. O'Hagan, J. Org. Chem., 2009, 74, 7168 - 7171.6) L. Hunter, P. Kirsch, A. M. Z. Slawin, D. O’Hagan, Angew. Chemie. Int. Ed., 2009, 48, 5457 - 5460.7) N. E. J. Gooseman, D. O`Hagan, M. J. G. Peach, A. M. Z. Slawin, D. J. Tozer, R. J. Young, Angew. ChemieInt. Ed., 2007, 46, 5904 - 5908.8) N. Campbell, D. L. Smith, A. P. Reszka, S. Neidle , David O’Hagan, Org. Biol. Chem, 2011, in press

L5

„Evolution of a Synthetic Strategy Towards the Unnatural Enantiomer of thePolyol/Polyene Antibiotic Nystatin A1:

The -Lactone Approach to 1,3-Diols and Chemoselective Hydrogenations of -Ketocarboxylic Acid Derivatives“

Reinhard Brückner, Universität Freiburg, Germany

„Why are polyol/polyene antibiotics constituted and configured the way they are?“ is a question, which we want tohelp answering by synthesizing a small library of constitutional and configurational isomers of the aglycon (1) ofthe polyol/polyene antibiotic known since the longest time: nystatin A1.

1

O

OHOOHOHOH

OH

OH

OH

O

HO

HOOC

OH

The library shall consist of the unnatural products ent-1, its diastereomer 2, the unnatural enantiomer ent-2 ofamphotericinolide B, and the diastereomer 4 of the latter.

O

HO O OH OH OHN

OHN

OH

OH

O

OH

COOH

OH

OHA

OHA

ent-1, 2: OHN present, OHA absent, C=C bond in the polyene moietyent-3, 4: OHA present, OHN absent, CC bond in the polyene moiety

compounds 2 and 4 shall have wedged instead of hatched bonds where highlighted

The polyol moiety of the targets 1-4 shall be generated by asymmetric C=O hydrogenations of the bis(-ketoester)5 as a late common intermediate.

O O O

O

O

O

O O

OMe

O5

Me3Si

The synthesis of 5 relies on a stereoretentive -lactone1,3-diol degradation. Processing 5 at one terminusdifferently than at the other made it desirable to investigate first the chemoselectivity of asymmetrichydrogenations of mixtures of two -ketocarboxylic acid derivatives and try to affect them one by one.

L6

News on an Old Puzzle – Chlorophyll Breakdown in Leaves and Fruit

Bernhard Kräutler

Institute of Organic Chemistry & Centre of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria

The seasonal metabolism of the chlorophylls is probably the most visual sign of life on earth,

observable even from outer space. It is estimated that more than 109 tons of chlorophyll (Chl)

are biosynthesized and degraded every year on the earth. The appearance of the green plant

pigments in spring and their disappearance in the autumnal foliage of deciduous trees and in

ripening fruit belong to the most colorful and fascinating natural phenomena.

Chl-breakdown has been an enigma until about 20 years ago. Botanical and chemical studies

have meanwhile revealed many aspects of how Chl is broken down in de-greening leaves and

ripening fruit: a largely ‘common’ path provides colourless linear tetrapyrroles, which we call

‘non-fluorescent’ Chl-catabolites (NCCs).[1] In yellow, ripe bananas, in contrast, a fascinating

‘blue glow’ results from accumulation of fluorescent Chl-catabolites (FCCs). FCCs typically

are short lived intermediates of Chl-breakdown that precede the NCCs. However, banana-

FCCs are chemically persistent due to specific natural ‘caging’ of a critical acid function.

Chl-breakdown has been suggested to be a detoxification process, mainly. Our findings

suggest it to generate linear tetrapyrroles that are likely to have a biological impact.

[1] S. Moser, T. Müller, M. Oberhuber, B. Kräutler, Chlorophyll Catabolites - Chemical and

Structural Footprints of a Fascinating Biological Phenomenon, Eur. J. Org. Chem. 2009, 21.

Posters / Abstracts

P1 Mauro F. A. AdamoEnantioselective Organocatalytic Addition of Bisulfite to Activated Alkenes

P2 Ahmed AlaghaMetal Complexes of Cyclic Hydroxamates. Synthesis and Crystal Structures of 1 and ItsMetal Complexes

P3 Sara ArfaeiDesign, Synthesis and Biological Evaluation of New (E)- and (Z)-1,2,3-triaryl-2-propen-1-ones as Selective COX-2 Inhibitors

P4 Swagata BanerjeeSynthesis and Photophysical Evaluation of a novel 4-amino-1,8-naphthalimidederivative as DNA binder

P5 Caroline BarthTotal Synthesis and Biological Evaluation of Novel Leukotrienes and Lipoxins Analogues

P6 Gea BelliniDesign and Synthesis of Novel Unnatural C-Nucleosides

P7 Lorraine BlackmoreNovel Molecular Dyes For Labelling Synthetic Peptides

P8 Filippo BonaccorsiApproaches Towards The Synthesis of Lewisb Hexasaccharide Glycosil Donors

P9 Tara BrightProduction of Mammalian Drug Metabolites By Streptomyces

P10 Michael P. CarrollDevelopment of an Asymmetric Synthesis of Isoflavanones

P11 Jennifer ClearyExpression of The Catalytic Domain of Urokinase Plasminogen Activator: A Target ForCancer Drugs

P12 Tadhg CotterIdentification of Novel Cancer Chemotherapeutic Agents: Design, Synthesis andEvaluation of Dual Targeting Agents for Heat Shock Protein (Hsp90) and Tubulin

P13 Lydie CoulombelConversion of Phenols to Catechols Using Bacterial Cells Expressing A Hydroxylase

P14 Kerri CrosseyPhosphorodiamidites: Synthesis in Ionic Liquids and Application to Arbuzov Chemistry

P15 Robin DalyNovel Synthetic Glycoporphyrins for use as Photodynamic Therapy Agents

P16 Katalin DaragicsSynthesis of Orthogonally Protected Lipopolysaccharide Structures From Neisseriameningitides

P17 Anthony DeallyNovel Achiral Indole-Substituted Titanocenes: Synthesis and Preliminary CytotoxicityStudies

P18 Robert W. DevineDesign and synthesis of novel compounds as potential therapeutics for Type-IIDiabetes Mellitus.

P19 Paolo DisettiCatalytic Enantioselective 3+2 Cycloaddition of Isocyanide Esters to 4-Nitro-5-styrylisoxazoles

P20 Niamh A.DolanThe Synthesis of Quinine-Based, Quinolone and Organotin Compounds and TheirEvaluation Against Gram-positive and Gram-negative Bacteria.

P21 Katherine S. DunneStereoselective Synthesis and Enzymatic Refinement of P-StereogenicPhosphonamidate Protide Drug Precursors

P22 Mothi M. Ebrahim1,3-Dipolar Cycloaddition of Silyl Nitronates to Meso-Tetraaryl Porphyrins

P23 Bill C. EganDesign of Chromene Based Compounds With Affinity For Steroid Hormone Receptors

P24 Robert B. P. ElmesQuaternarized pdppz: Synthesis, DNA-Binding and Biological Studies of a Novel dppzDerivative That Causes Cellular Death Upon Light Irradiation

P25 Viviane FournièreSynthesis of The Lewisb Family Pentasaccharide

P26 Sandra GannonThe Synthesis and Evaluation of DNA Targeting Hybrid Drugs as New AntitumourAgents

P27 Kimberly GeogheganCyclic Sulfonamides: Their Regioselective Formation and Synthetic Applications

P28 Anja GlinschertSynthesis of Monodeoxy Trisaccharides Recognised By Calreticulin/Calnexin

P29 Darren GriffithNovel Platinum Drug Candidate With Dual DNA Binding and Histone DeacetylaseInhibitory Activity

P30 Gavin HaberlinStereoselective Synthesis and Biological Evaluation of Novel Aromatic Lipoxin A4

Analogues

P31 Brian HigginsTowards the Development of Antitubercular Drugs: Synthesis of Analogues ofMycothiol

P32 Martin Hollinger and Fana AbrahaLinear and Convergent Synthesis of Mucin O-Glycan Core Structures For TheInvestigation of Their Binding to Gut Bacteria

P33 Angela S. InfantinoSynthesis of Fluorinated Oligosaccharides For Interaction Studies With Lectins

P34 Brendan KellyGuanidino Pyridines: Computational Study and Synthesis

P35 Graeme KellySynthesis of a Heterodimer Peptide Targeting Cancer Cells

P36 Patrick M. KellyThe Design and Synthesis of Dual-Acting Estrogen Receptor Conjugates

P37 Naseem KhanDerailment of a Dodecaketide Intermediate From An Engineered AmphotericinPolyketide Synthase

P38 Oxana KotovaLanthanide Luminescent Displacement Assays: Selective Sensing of Fe(II) Using Eu(III)–cyclen Complexes In Aqueous Solution

P39 Jaya S. KudavalliDynamic Resolution of Phosphines Under Appel Conditions: Mechanistic Insights FromUse of a Cyclic Phosphine and BINOL As Alcohol

P40 Mark LongDevelopment of a Practical Synthesis of a 13C6 Labelled L-Fucoside from L-Galactose

P41 Christine MaraDesign and Evaluation of Novel Antiparasitic Agents Targeting Parasite Tubulin

P42 Dennis McCartneySynthesis of New Bidentate N, O Axially Chiral Ligands For The AsymmetricDehydrative Cyclisations of ɷ-Hydroxy Allyl Alcohols

P43 Yvonne McNamara9, 10-Dihydro-9, 10-ethanoantracenes: Synthesis and Anti-Proliferative Activity inBurkitt Lymphoma Cell Lines

P44 Ivano MessinaSynthesis of stable Acetyl ADPR analogues

P45 Ludovic MilhauNew Substrates for Rhodium Catalysed Asymmetric Hydroboration using P-N Ligands

P46 Maria MocciaDesign and synthesis of novel PNA analogues

P47 Susan MolloyEngineering a Monooxygenase Enzyme For Enhanced Activity Towards Alkenes

P48 Cathal F. MurphyIsolation and Synthesis of Bioactive Natural Products from Marine Sources

P49 Niamh MurphySynthesis of α-S-Galactosylceramides As Potential Vaccine Adjuvants

P50 Aisling Ni CheallaighApproaches to The Synthesis of Streptococcus Pneumoniae Type 1 Cps Repeating Unit

P51 Maeve O’NeillTowards The Synthesis of 1-Aminocyclopropane-1,2-Dicarboxylic Aicd, a PotentialAntimalarial Agent

P52 Shane O’NeillEnantioselective Copper Catalysis in the Intramolecular Buchner Reaction

P53 Edyta PaszkoLiposomal Formulations of Photosensitizers For Photodynamic Cancer Therapy

P54 Lara PesSynthesis of Conformationally Restrained Non-Natural Dipeptides

P55 Teodolinda PetrilloCloning and Expression of The Catalytic Domain of BACE1: A Drug Target For TheTreatment of Alzheimer Disease

P56 Daniela Quaglia and Matteo PoriStrategies For The Immobilization of Horse Liver Alcohol Dehydrogenase

P57 Dilip K. RaiCharacterisation of Polyacetylenes In Carrot Extracts Using Electrospray IonisationQuadrupole Time of Flight Mass Spectrometry

P58 Kamalraj V. RajendranAn Easy Short Preparation of Pentachloroacetone and Tetrachloroacetone By SelectiveDechlorination of Hexachloroacetone Under Appel Conditions

P59 Kamalraj V. RajendranP-stereogenic Phosphorus Compounds: 31P-NMR Studies On The ReactiveIntermediates In The Asymmetric Appel Reaction

P60 James ReckSynthesis of Unnatural C-nucleosides for DNA Based Catalysis

P61 Philip RedpathTandem ENE/IMSC For The Synthesis of Pyranosyl C-Nucleosides

P62 Barbara Richichi and Heather HoranTowards a N. meningitidis Glycoconjugate Vaccine: Synthesis of DifferentiallyProtected Disaccharide Analogues of Lipid A.

P63 Keith RobertsonA Novel Synthesis of Rare 4-methylenecyclohex-2-enone

P64 Aoife RyanSynthesis of Porphyrin Oligomers For Applications In Photodynamic Therapy

P65 Dominique F. SchreiberApplicability of BETA-diketiminate ruthenium(II)-arene Complexes In HomogeneousLewis Acid Catalysis of Diels-Alder Reactions

P66 Natalia N. SergeevaSmall Molecules For Fluorescence Imaging and Cancer Diagnostics

P67 Dean St.MartA Novel Organic Fluorophore and its Potential Application as a Biological Probe

P68 Mark TallonSynthesis and Antibacterial Activity of a Series of Carbohydrate Fatty AcidGlycoconjugates

P69 Rebecca UlcSynthesis of Capsular Polysaccharide Structures of Cryptococcus neoformans

P70 Shu WangThe Synthesis and Investigation of β-Lactam Ring as Scaffold for Novel BioactiveCompounds

P1ENANTIOSELECTIVE ORGANOCATALYTIC ADDITION OF

BISULFITE TO ACTIVATED ALKENES

Francesco Fini, Maria Moccia, Michela Scagnetti and Mauro F. A. Adamo

Centre for Synthesis and Chemical Biology (CSCB), Royal College of Surgeons in Ireland,Department of Medicinal and Pharmaceutical Chemistry, 123 St Stephen’s Green, Dublin 2,

Dublin.

email: [email protected]

Herein we describe the discovery of an enantioselective methodology for the addition ofbisulfate to alkenes, that is catalysed by amines. Typically, chalcone 1 reacted with NaHSO3

in presence of amine 3 (Scheme 1) to give sulfonic acid 2 in 95% yield and over 90% ee; todate this constitutes the unique example of enantioselective addition of bisulfite to alkenes.The reaction of bisulfite with -unsaturated ketones, esters, and amides has been known forover a century as a means to prepare sulfonic acids1.

Scheme 1

aq. NaHSO3 (1.1 equiv)amine 3 (0.05-0.1 equiv)

CH3OH/THF, RT, 12 h.1 2

O O SO3H

N

NHN

CH3O

SNH

F3C

CF3

95%yield93-99% ee

3

However, only a few applications of this reaction have been reported due to the harshness ofconditions required. Highly activated (disubstituted) enones were necessary, the reactionsrequiring long reaction times,2 use of high temperatures, microwaves3 or radical initiators.Therefore, the addition of bisulfite to alkenes is at the present an unpractical yet potentiallyuseful reaction. Our conditions are mild, don’t require heating or cooling and avoid the use ofradical initiators. The scope of reaction is wide including cyclic and acyclic alkenes, bearingan electron withdrawing group such as ester, carbonyl, cyano and nitro. Sulfonic acidsobtained have potentials as: (a) surfactants (b) chemicals in drug discovery (c) chemicalintermediates (d) resolving agents (Dutch resolution).

References:

[1] (a) Beilstein, F. K. et Al. Chem. Ber. 1885, 18, 482. (b) Dodge, F. D. J. Am. Chem. Soc. 1930, 52, 1724[2] [(a) Kellogg, R. M.; et Al. Synthesis 2003, 10, 1626; (b) Baczko, K.; et Al. J. Chem. Soc., Perkin Trans.2 2001, 2, 2179. (c) Hejchman, E.; et Al. J. Med. Chem. 1995, 38, 3407. (d) Pfoertner, K. H. Helv. Chim. Acta1980, 63, 664.].[3] Crawley, M. L., et Al. Org. Lett., 2005, 7, 5067.]

P2

METAL COMPLEXES OF CYCLIC HYDROXAMATES. SYNTHESIS

AND CRYSTAL STRUCTURES OF 1 AND ITS METAL COMPLEXES

Ahmed Alagha1, Laavanya Parthasarathi 1, Declan Gaynor 1, Helge Müller-Bunz 2, and KevinB. Nolan 1

Centre for Synthesis and Chemical Biology, 1Department of Pharmaceutical and MedicinalChemistry, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2 and 2Schoolof Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.

Email: [email protected]

The attempted acetylation of antranilic hydroxamic acid (2-aminobenzohydroxamic acid) as apossible dual inhibitor of the catalytic sites in prostaglandin-H-synthase (PGHS),1,2 gave thecyclic hydroxamic acid, Cha 1. The complexes Fe(Cha)2(Cl)(H2O).7/2H2O, Co(Cha)2(EtOH)2,Ni(Cha)2(EtOH)2, 2, Cu(Cha)(H2O)(Cl) and Zn(Cha)2(H2O), have been synthesised and theirstructures determined by X-ray crystallography. The X-ray data confirmed coordination byCha- through the carbonyl and deprotonated hydroxamate oxygen in all cases. The M-O(hydroxamate) bonds are shorter than the M-O(carbonyl) bonds by between 0.0930 Å for theCo(II) complex to 0.0448 Å for the Ni(II) complex. The geometries of all complexes conformto the coordination requirements of the particular metal ion involved. Speciation studies showthat ChaH is much more acidic than related acyclic hydroxamic acids and that its metalcomplexes are correspondingly less stable.

2

References:

[1] C. J. Marmion, D. Griffith, K. B. Nolan, Eur. J. Inorg. Chem., 2004, 15, 3003-3016.[2] J Lee, A. J. Chubb, E. Moman, B. M. McLoughlin, C. T. Sharkey, J. G. Kelly, K. B. Nolan, D. J.

Fitzgerald, M. Devocelle, Org. Biomol. Chem., 2005, 3, 3678 - 3685.

P3

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW (E)-AND (Z)-1,2,3-TRIARYL-2-PROPEN-1-ONES AS SELECTIVE COX-2

INHIBITORS

Sara Arfaei a,b, Afshin Zarghi b, Mary J Meegan a

a) Department of Pharmaceutical Chemistry, School of Pharmacy and PharmaceuticalSciences, Trinity college Dublin, Dublin 2, Ireland

b) Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid BeheshtiUniversity of Medical Sciences, Tehran, Iran


Selective COX-2 inhibitors are known as a group of drugs which have the potent anti-inflammatory and analgesic effects of classical NSAIDs with less GI adverse effects. Apartfrom their anti-inflammatory effects, they have recently shown to possess anticancerproperties. They have also shown to reduce the progression of Alzheimer’s disease.[1,2] Thesecompounds belong to a class of diarylheterocycles having vicinal diaryl moieties attached to acentral heterocyclic ring scaffold in conjunction with a COX-2 pharmacophore such as apara-SO2NH2, or a para-SO2Me, substituent on one of the phenyl rings [3]. Celecoxib androfecoxib are two typical selective COX-2 inhibitors in this class (COXIBs). However,several compounds possessing acyclic central systems such as triaryl olefinic structures havealso been designed and identified that exhibit COX-2 inhibitory activity [4-8].In this study, a group of (E)- and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing amethylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring weresynthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 propenonemoiety. The Z-propenones were found to be more potent and selective than their E-isomers forCOX-2 inhibitory activity. A molecular modeling study was also performed where E- and Z-1-(4-(methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one were docked in the binding site ofCOX-2 enzyme. The structure activity data acquired indicate that the geometry of propenoneand also the type of substituents on the C-3 propenone are important for COX-2 inhibitoryactivity.

References:[1] Williams, C.S.; DuBois, R.N. Am. J. Physiol. 1996, 270, G393-400.[2] Konturek, P.C.; Kania,J.; Burnat,G.; Hahn, E.G.; Konturek, S.J. J. Physiol. Pharmacol. 2005, 56, 57.[3] Talley, J. J. Prog. Med. Chem. 1999, 36, 201.[4] Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E. Bioorg. Med. Chem. Lett. 2004, 14, 1953.[5] Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E.; McDonald, R. J. Med. Chem. 2004, 47, 6108.[6] Praveen Rao, P. N.; Chen, Q.-H.; Knaus, E. E. Bioorg. Med. Chem. Lett. 2005, 15, 4842.[7] Zarghi, A.; Kakhgi, S.; Hadipoor, A.; Daraee, B.; Dadras, O.; Hedayati, M. Bioorg. Med. Chem. Lett. 2008,

18, 1336.[8] Zarghi, A.; Arfaee, S.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem. 2006, 14, 2600.

P4

Synthesis and Photophysical Evaluation of a novel 4-amino-1,8-naphthalimide derivative as DNA binder

Swagata Banerjee, John M. Kelly* and Thorfinnur Gunnlaugsson*School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin,

Dublin 2, Ireland

email: [email protected], [email protected].

The development of small molecules capable of binding to DNA and exhibiting anticanceractivities has received much attention in recent times.[1,2] In this context, 1,8-naphthalimidederivatives represent an important family of DNA binders that exhibit their antitumour effectsboth in vitro and in vivo.[3-6] Photoexcitation of various naphthalimide derivatives have alsobeen shown to induce sequence selective DNA strand cleavage with the site of cleavage foundto be modulated by the substitution present on naphthalimide ring.[7] This project focuses onthe development of a novel cationic DNA binder 1 (Figure 1) derived from 4-amino-1,8-naphthalimide. The pyridinium side chain of compound 1 imparts high water solubility andfavours electrostatic interaction between negative phosphate backbone of DNA and thenaphthalimide ligand. The binding interactions of 1 with mononucleotides, salmon testes (st)DNA, and homopolymeric nucleotide sequences have been evaluated by photophysicaltechniques including UV-vis, fluorescence, circular and linear dichroism. These resultsshowed that 1 exhibits high affinity towards double-stranded DNA (~105 M-1) with apreference for A-T rich sequences.

Figure 1: (2-(N-Pyridinium)-ethyl)-4-amino-1,8-naphthalimide (1)References:[1] Ma, H.; Zhang, M.; Zhang, D.; Huang, R.; Zhao, Y.; Yang, H.; Liu, Y.; Weng, X.; Zhou, Y.; Deng, M.; Xu,L.; Zhou, X., Chemistry - An Asian Journal. 2010, 5, 114.[2] Vos, J. G.; Kelly, J. M., Dalton Trans. 2006, 4869.[3] Qian, X.; Li, Y.; Xu, Y.; Liu, Y.; Qu, B., Bioorg. Med. Chem. Lett. 2004, 14, 2665.[4] Li, Y.; Xu, Y.; Qian, X.; Qu, B., Tetrahedron Lett. 2004, 45, 1247.[5] Veale, E. B.; Frimannsson, D. O.; Lawler, M.; Gunnlaugsson, T., Org. Lett. 2009, 11, 4040.[6] Veale, E. B.; Gunnlaugsson, T., J.Org. Chem. 75, 5513.[7] Saito, I.; Takayama, M.; Sugiyama, H.; Nakatani, K.; Tsuchida, A.; Yamamoto, M., J. Am. Chem.Soc. 1995, 117, 6406.

P5

Total Synthesis and Biological Evaluation of NovelLeukotrienes and Lipoxins Analogues

Prof. Pat Guiry* and Caroline BarthCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

University College Dublin, Dublin 4, Ireland

E-mail: [email protected] and [email protected]

Leukotrienes (LTBs) and Lipoxins (LXBs) are two groups of biologically activemolecules derived from arachidonic acid which are implicated in many types of inflammationincluding psoriasis and inflammatory bowel disease.1

However, these molecules undergo rapid metabolism due to the unstable triene system. Hencewe aim to design a set of analogues which contain a highly stable aromatic ring in place of thetriene system. This should bring the required stability and also a good tool for the introductionof various substituents, which would enable us to tune the activity of the molecule.

There are two distinct projects. The first one is the synthesis of Leukotriene analogues(from both LTB3 and LTB4), where the two chains are oriented in ortho-position on thearomatic ring (Scheme 1). The second project is the synthesis of Lipoxins B4 (LXB4)analogues (Scheme 2). Inspired by existing procedures - the Guiry research group hasconsiderable experience working on related Lipoxin analogues2 - we started the synthesis of aseries of ortho- and the meta-oriented analogues for SAR studies.

Scheme 1

Scheme 2

1 Miyahara N.; Miyahara S.; Takeda K.; Gelfand E.W. Allergology International 2006, 55, 91-972 O’Sullivan, T. P.; Vallin, K. S. A.; Shah, S. T. A.; Fakhry, j.; Maderna, P.; Scannell, M.; Sampaio, A. L. F.;Perretti, M.; Godson, C.; Guiry, P. J. J. Med. Chem. 2007, 50, 5894.

P6

DESIGN AND SYNTHESIS OF NOVEL UNNATURAL C-NUCLEOSIDES

Gea Bellini, Maria Moccia and Mauro F. A. Adamo


Dublin.


Artificial DNA for alternative DNA base pairing through metal complexation was recentlyreported in literature.1,4 Inspired by previous results1-5 we designed and synthesized novel C-Nucleosides bearing specific functional groups on the anomeric position. The ability of ournovel C-Nucleosides to act as natural nucleobases, replacing hydrogen-bonded natural basepairs, will be investigated. Their ability to incorporate divalent metals, forming square planarcomplexes, will also be studied. The final aim of the project will be the nanoassembly ofmultimetal arrays along the DNA helix axis to achieve molecular wires and magnets.

R = O, NH

O

O

O

PO

-O

RCuO

O

R

O

O

O

PO

-O

References:

1. Tanaka, K., Tengeiji, A., Kato, T., Toyama, N., Shiro, M.; Shionoya, M. J. Am. Chem. Soc. 2002, 124,12494-12498.

2. Tanaka, K., Shionoya, M. J. Org. Chem. 1999, 64, 5002-5003.3. Tanaka, K., Shionoya, M. Coord. Chem. Rev. 2007, 251, 2732-2742.4. Tanaka, K., Tasaka, M., Cao, H., Shionoya, M. Eur. J. Pharm. Sci. 2001, 13, 77-83.5. Adamo, M. F. A., Pergoli, R. Org. Lett. 2007, 9, 4443-4446.

P7

NOVEL MOLECULAR DYES FOR LABELLING SYNTHETICPEPTIDES

Marc Devocelle1, Tia E. Keyes2 and Lorraine Blackmore 1,2

1. Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and MedicinalChemistry, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland

2. School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland

email: [email protected], [email protected]

Luminescent dye molecules capable of passive cell delivery may be used as molecular probesfor example in cellular imaging. Ruthenium polypyridyl complexes have uniquephotophysical characteristics which make them potentially invaluable as probes for cellularimaging. They are long lived, exhibit polarised luminescence, have good photostability, redemission wavelengths and large stokes shifts and oxygen sensitivity. Although, they havelong been muted as potentially useful, application of ruthenium polypyridyl complexes in thisregard has been very limited. Recent work by our group has reported that polyargininelabelled ruthenium complexes efficiently and rapidly transport across the cell membrane intothe cytoplasm.[1, 2] Such chromophores provide unique opportunities for imaging dynamicprocesses in living cells avoiding limitations associated with fixation.

In this contribution, we describe how we are refining these synthetic strategies toenvironmentally sensitive phosphors which can be targeted within the cell. These dyes will beused to label synthetic peptides with known sub cellular localisation to validate their use andextend ultimately their application to new peptide sequences.

We report on the synthesis and characterisation of a ruthenium (II) complex[Ru(dpp)2PIC]ClO4 and [Ru(bpy)2PIC]ClO4 covalently attached to nuclear localisation signalpeptides[3] and mitochondrial targeting peptides.[4,] The spectral (absorption and emission) andphotophysical (fluorescence lifetime) properties of this metal-ligand peptide complex aredescribed. Preliminary results on their application in cell imaging are also presented.

References:

[1] L. Cosgrave, M. Devocelle, R. J. Forster, T. E. Keyes. Chem Comm, 2010, 46, 103.[2] Y. Pellegrin, U. Neugebauer, M. Devocelle, R. J. Forster, W. Signac, N. Moran, T. E. Keyes. Chem

Commun, 2008, 42, 5307.[3] A. D. Ragin, R. A. Morgan, J. Chmielewski. Chem Biol, 2002, 8, 943.[4] J. S. Mader, D. W. Hoskin. Expert Opin. Investig. Drugs, 2006, 15, 933.

P8

APPROACHES TOWARDS THE SYNTHESIS OF LEWISb

HEXASACCHARIDE GLYCOSIL DONORS

Filippo Bonaccorsi and Stefan OscarsonCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

University College Dublin, Belfield, Dublin 4, Ireland


Helicobacter Pylori is a gastric pathogen which induces chronic gastric inflammation, theinflammation may progress to severe forms of gastroduodenal diseases such as peptic ulcer and gastricadenocarcinoma1. The Helicobacter Pylori infection occurs with the binding between carbohydratesantigens expressed on the gastric mucosa, such as H-1 and Leb (Figure 1), and adhesins expressed bythe pathogen, such as BabA2,3.

OOH

O OHO

O

HO OH

OH

OH

OOO

O NHAc

OH

OOH

HO O

OH

OHHO

O

HO

O

OH

OH

OH

Gastric Mucosa

Figure 1

Several synthesis of the Leb antigen and its conjugates derivatives have already been reported by Danishefsky4,5

using glycals as glycosil donors and Oscarson6,7 using bromides and thioglycosides.In this work we present a new method to synthesize protected forms of the Lewis b structures as glycosyl donors(Figure 2) from readily available sugars, to employ for the synthesis of larger glycosyl structures.

OOP

O OPO

O

PO OP

OP

OP

LOO

O NHAc

OP

OOP

PO O

OP

OPPO

O

PO

O

OP

OP

OP

OOH

HO OHO

O

HO OH

OH

OH

OH

OOH

HO OHOH

OH

OHO

HOHO NH2

OH

HO

O

OH

OH

HO

Figure 2

References:

[1] Cover, T.L.; Berg, D.E.; Blaser, M.J.; Mobley, H.T.L.; H. Pylori Pathogenesis. In Principles of bacterialpathogenesis. Ed. Groisman, E.A. (Academic Press, San Diego, California, 2001). 510-18.[2] Boren, T.; Falk, P.; Roth, K.A.; Larsson, G.; Normak, S. Science 1998, 262, 1892-5.[3] Ilver, D.; Arnqvist, A.; Ogren, J.; Frick, I-M.; Kersulyte, D.; Incecik, E.T.; Berg, D.E; Covacci, A.;

Engstrand, L.; Boren.; Science 1998, 279, 373-7.[4] Randolph, J.T.; Danishefsky, S. Angew. Chem., Int. Ed 1994, 33, 1470-73.[5] Randolph, J.T.; McClure, K.F.; Danishefsky, S. J. Am. Chem. Soc. 1995, 117, 5701-11; 5712-19.[6] Chernyak, A.; Oscarson, S.; Turek, D. Carbohydr. Res. 2000, 329, 309-16.[7] Lahman, M.; Bulow, L.; Teodorovic, P.; Guback, H.; Oscarson, S. Glycoconj. J. 2004, 21, 251-56.

P9

PRODUCTION OF MAMMALIAN DRUG METABOLITES BYSTREPTOMYCES

Tara Bright, Benjamin Clark and Cormac Murphy

UCD School of Biomolecular and Biomedical Science, Centre for Synthesis and ChemicalBiology, Ardmore House, University College Dublin, Belfield, Dublin 4, Ireland.


This project focuses on using bacteria to produce human metabolites of flurbiprofen and otherfluorinated drugs. Bacterial cytochromes P450 have been widely studied and are known fortheir oxidative metabolism of drugs.[1] Presented here is a summary of our work to date, inwhich several Streptomyces species were screened for their ability to produce hydroxylatedmetabolites of the anti-inflammatory drug flurbiprofen (1). Seven strains produced 4’-hydroxyflurbiprofen (2) and three strains also produced 3’methoxy-4’-hydroxy-flurbiprofen(3). When 19F NMR was carried out on extracted supernatants from S.lavenduligriseus andS.rimosus two unknown resonances where observed. These were purified by HPLC andidentified as the novel fluorometabolites flurbiprofenamide (5) and 7’-hydroxyflurbiprofenamide (6) after MS and NMR analyses.

6

S. lavenduligriseus

1 5 6

S. lavenduligriseus

1 5

References:

[1] P. Shrestha, T. Oh, K. Liou, J. K. Sohng, Appl Microbiol Biotechnol 2008, 79:555–562

P10

Development of an Asymmetric Synthesis of Isoflavanones

Michael P. Carroll and Patrick J. GuiryUCD Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis andChemical Biology, School of Chemistry and Chemical Biology, University College Dublin,

Belfield, Dublin 4, Ireland


Isoflavanones (Fig.1) are a class of naturally occurring plant secondary metabolites whichdisplay a range of medicinal properties, including anti-cancer activity.1 Despite their potentialas therapeutic agents and the many reported syntheses of isoflavanones,2 only onestereoselective synthesis has been developed.3 This synthesis employed the use of chiralauxiliaries. A more efficient approach could be envisioned using asymmetric catalysis.

Fig 1. General structure of isoflavanones.

The focus of this research project is the development of an expedient asymmetric synthesis ofisoflavanones, using a lead mediated arylation,4 followed by a novel palladium-catalysedtransformation which can generate the required stereocenter (Scheme 1). This poster willhighlight our recent progress in this area.

Scheme 1. Palladium-catalysed enantioselective transformation to yield enantioenrichedisoflavanones.

References:

1. M. Luo, X. Liu, Y. Zu, Y. Fu, S. Zhang, L. Yao, T. Efferth, Chem-Biol. Interact. 2010, 151-160

2. (a) R. B. Bradbury, D. E. White J. Chem. Soc. 1 1953, 871-876, (b) B. S. Kirkiacharian, J. Chem. Soc. Chem.Commun. 1975, 162-163, (b) D. M. X. Donnelly, J. P. Finet, B. A. Rattigan, J. Chem. Soc. Perkin Trans. 1 1993,1729-1735 (d) F. Bellina, T. Masini, R. Rossi, Eur. J. Org. Chem. 2010, 1339-1344

3. J. L.Vicario, D. Badia, E. dominguez, M. Rodriguez, L. Carrillo, Tetrahedron Lett. 2000, 41, 8297-8300

4. Arylation with ArPb(OAc)3 has been well documented : (a) D. H. R. Barton, D. M. X. Donnelly, J. P. Finet, P.J. Guiry, Tetrahedron Lett. 30, 1539-1542, (b) D. H. R. Barton, D. M. X. Donnelly, J. P. Finet, P. J. Guiry, J.Chem. Soc., Perkin Trans. 1, 1992, 1365-1375 (c) D. H. R. Barton, D. M. X. Donnelly, J. P. Finet, P. J. Guiry, J.Chem. Soc., Perkin Trans. 1, 1994, 2921-2926

P11

EXPRESSION OF THE CATALYTIC DOMAIN OF UROKINASEPLASMINOGEN ACTIVATOR: A TARGET FOR CANCER DRUGS

Jennifer Cleary and J. Paul G. Malthouse*

UCD Conway Institute of Biomolecular and Biomedical Research, UCD Centre for Synthesisand Chemical Biology, UCD SEC Strategic Research Cluster, School of Biomolecular and

Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.

Email: [email protected], [email protected]

Urokinase plasminogen activator (uPA) is a trypsin-like serine protease. It has been reportedto be involved in tumorigenesis, cellular proliferation, degradation of extra cellular matrix,cell migration and adhesion, angiogenesis and intravasation [1]. It is also a diagnostic markerfor breast cancer. Therefore it is a good target for anti cancer drugs [1, 2]. It has been shownthat peptide derived glyoxal inhibitors can be potent and specific inhibitors of the serineproteases [3-6]. Therefore the ultimate aim of this project is to synthesise glyoxal inhibitors ofuPA that can be used in cancer chemotherapy. We hope to use NMR to study inhibitorbinding which should allow us to optimise inhibitor design. However, uPA is usuallyexpressed as a 53 kDa protein consisting of a catalytic domain, a growth factor domain and akringle domain. Such a large protein would be difficult to study by NMR. A chimeric form(Mr 34000) of the catalytic domain and hirudin has been expressed in very low yields [7]. Inthis project we hope to express the catalytic domain (residues 144-412 plus his tag, Mr 31200)in E.coli cells and prepare large amounts of the pure low molecular weight protein for NMRstudies. The catalytic domain of uPA has been amplified from the chimeric 34kDa form usingPCR. This gene has been cloned into the pet21a an expression vector and expressed in BL21DE3 competent cells. We show that we have expressed the catalytic domain and that we haveadded a hexahistidine tag onto the end of the protein that allows the protein to be purified bynickel chromatography.

References:

[1] Duffy, M.J. (2004). The urokinase plasminogen activator system: role in malignancy. Curr. Pharm. Des.10, 39-49.

[2] Crippa, M.P. (2007). Urokinase-type plasminogen activator. Int. J. Biochem. Cell Biol. 39, 690-4.[3] Djurdjevic-Pahl, A., Hewage, C. and Malthouse, J.P.G. (2002). A 13C-NMR study of the inhibition of

delta-chymotrypsin by a tripeptide-glyoxal inhibitor. Biochem. J. 362, 339-347.[4] Malthouse, J.P. (2007). 13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization

by the serine proteinases:. Biochem. Soc. Trans. 35, 566-70.[5] Spink, E., Cosgrove, S., Rogers, L., Hewage, C. and Malthouse, J.P.G. (2007). 13C and 1H NMR studies

of ionizations and hydrogen bonding in chymotrypsin-glyoxal inhibitor complexes. J. Biol. Chem. 282,7852-61.

[6] Howe, N., Rogers, L., Hewage, C. and Malthouse, J.P.G. (2009). Oxyanion and TetrahedralIntermediate Stabilization by subtilisin: detection of a new tetrahedral adduct. Biochimica et BiophysicaActa (BBA) - Proteins & Proteomics 1794, 1251-1258.

[7] Bi, Q., Cen, X., Huang, Y. and Zhu, S. (2002). Construction and characterization of trifunctional single-chain urokinase-type plasminogen activators. Eur. J. Biochem. 269, 1708-1713.

P12Identification of Novel Cancer Chemotherapeutic Agents:

Design, Synthesis and Evaluation of Dual Targeting Agents for Heat Shock Protein(Hsp90) and Tubulin

Tadhg Cotter * and Mary J. Meegan

School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology,Panoz Institute, Trinity College Dublin, Dublin 2.


An emerging trend in cancer treatment is the inhibtion of Heat Shock Protein 90 (Hsp90). Hsp90 hasbeen recognized to function in the protection of cells when stressed by elevated temperatures and inunstressed conditions, it assists in regulation of cell signalling, folding, transport, maintenance anddegradation of proteins. Its involvement in multiple signalling pathways on which cancer cells dependfor growth and survival, makes it an attractive target [1, 2].

The discovery of a novel indazole-based scaffold which represents the “first-in-class” dualHsp90/tubulin binding compound was recently reported by our research group [3]. It followed thereport of a recent structure of an Hsp90 inhibitor (figure 1, structure A) which was the centre of thisdiscovery. This inhibitor contained a 3’,4’,5’-trimethoxyphenyl moiety, which is observed by manygroups as being required for binding of ligands in the colchicine binding site of Tubulin [4].Compound C (figure 1) was the novel dual inhibitor which was identified from this study.

Figure 1: Common 3’,4,’5’ trimethoxyphenyl pharmacophore: (A) tubulin inhibitor 3-arylthionindole, , (B) PU3analogue Hsp90 inhibitor, (C) Dual Hsp90/tubulin binding compound.

The objective of this research is to investigate the design, synthesis, structure-activity relationshipsand pharmacokinetics of a novel series of products which will incorporate the structural features ofnovel Targeting Agents for Hsp90 and Tubulin which are present in compound C. This approachpermits targeting the Hsp90 receptor and protein tubulin which are abundant in tumour cells.Currently, a series of analogues based on the initial hit compound C have been synthesised. Thepreliminary synthetic and structural studies will be presented.

[1] Chiosis, G; Neckers, L. ‘Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive’ ACS Chem.Biol. 2006, 1, 279-284[2] Neckers. L.; Lee, Y.S. ‘Cancer: the rules of attration’ Nature (London) 2003, 425, 357-359[3] Knox, Andrew J. S.; Price, Trevor; Pawlak, Michal; Golfis, Georgia; Flood, Chrostopher T.; Fayne, Darren;Williams, D. Clive, Meegan, Mary J.; Lloyd, David G. ‘Investigation of Ligand and Structure-Based VirtualScreening for the Identification of the First Dual Targeting Agent for Heat Shock Protein 90 (Hsp90) andTubulin’ J. Med. Chem. 2009, 52, 2177 – 2180[4] Gaukroger, K.; Hadfield, J. A.; Lawerence, N.J.; Nolan, S.; McGowan, A.T. ‘Structural requirements for theinteraction of combretastatins with tubulin: how important is the trimethoxy unit?’ Org. Biomol. Chem. 2003, 1,3033-3037

P13

CONVERSION OF PHENOLS TO CATECHOLS USING BACTERIAL CELLSEXPRESSING A HYDROXYLASE

Lydie Coulombel1, Louise C. Nolan1, Jasmina Nikodinovic-Runic1, Evelyn M. Doyle1 and

Kevin E. O’Connor*1

1UCD Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and ChemicalBiology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4,

Ireland


Substituted catechols are important aromatic compounds and are extensively used asprecursors in the chemical and pharmaceutical industrial processes such as the manufacture ofsynthetic flavours, antioxidants, antihypertensive drugs, plastics, polymers and dyes.[1]

Halocatechols are valuable intermediates in organic synthesis due to the relative ease ofhalogen substitution (in particular iodine and bromine moieties). However, the chemicalsynthesis of 4-substituted catechols is often complex and involves severe reaction conditions,poor regiospecifity and low product yield. This limitation has led to increased interest in themicrobial synthesis of these compounds.

4-Hydroxyphenylacetate (4-HPA) 3-hydroxylase (EC 1.14.13.3) of Escherichia coli W is atwo-component flavin-dependent monooxygenase that catalyzes the hydroxylation of 4-HPAinto 3,4-dihydroxyphenylacetate. While PHPA hydroxylase has recently been described toconvert tyrosol to hydroxytyrosol[2], the production of 4-substituted halocatechols from 4-substituted halophenols is a novel application for this enzyme. We have for the first timedeveloped a biocatalytic route for synthesizing gram quantities of 4-substituted halocatecholsat 5 l scale, based on whole cells E. coli BL21 (DE3) expressing recombinant 4-HPA 3-monooxygenase (HpaBC) from E. coli BL21 (DE3) (Fig. 1). Here we also investigate therecovery of 4-substituted halocatechols from aqueous media which has not been demonstratedpreviously.[3]

Figure 1. Biotransformation of 4-halophenols by E. coli BL21(DE3) cells expressing 4-hydroxyphenylacetate 3-monooxygenase (HpaBC)

References:[1] A. Schmid, J. S. Dordick, B. Hauer, A. Kiener, M. Wubbolts, B. Witholt Nature (London), 2001, 409,

258.[2] J. Achkar, A. Ferrandez. PCT Int. Appl., 2008, WO 2008064839 A2. (DSM IP Assets B.V., Neth.)[3] L. Coulombel, L. C. Nolan, J. Nikodinovic, E. M. Doyle, K. E. O’Connor, Appl Microbiol Biotechnol,

Online First™, November 6th 2010.

P14Phosphorodiamidites: Synthesis in Ionic Liquids and Application to

Arbuzov Chemistry

Kerri Crosseya, Christopher Hardacrea, Marie E. Migauda*

aQUILL, School of Chemistry and Chemical Engineering, Queens University Belfast, Belfast,Northern Ireland BT9 5AG

Organophosphorous compounds contribute a particular significance to many areas of modernorganic chemistry both industrially and medicinally. This includes their use in pesticides,fungicides, fire retardants and lubricants as well as chelating agents, stabilisers, antioxidantsand scale formation inhibitors.[1] Organophosphonates are also important syntheticprecursors to many biologically relevant materials.[2] The Michaelis- Arbuzov reaction is oneof the most versatile and extensively investigated pathways in organophosphorous chemistry;however the harsh reaction conditions often employed in this transformation means that thechoice of starting phosphorus reagent is limited.[3] The application of ionic liquids assolvents for promoting the Michaelis-Arbuzov rearrangement at ambient temperatures hasalready been documented in the literature [4] as has the use of ionic liquids for the synthesisand stabilisation of a range of reactive phosphoramidites.[5]

This project focuses on the use of ionic liquids for the synthesis of a range ofphosporodiamidites and their subsequent use in Arbuzov type reactions. This would affordaccess to novel phosphonates containing the P-N bond. DFT calculations have been used inorder to predict and validate the outcome of these reactions.

Ionic Liquid

iPr2

MeEtMorpholino

R'=

References:

[1] M., Gupta, A.K. and Kaushik, M. P., Tetrahedron Letters, 2006, 47, 3107-3109.[2] Kafarski, P., Lejczak, B., Phosphorous, Sulfur Silicon Relat. Elem., 1991, 63, 193. (b) Shi, E., Pei, C.,

Synthesis, 2004, 2995[3] Kedrowski, M. A., Dougherty, D. A., Org. Lett., 2010, 12, 3990-3993[4] Matveeva, E. V., Odinets, I. L., Kozlov, V. A., Shaplov, A. S., Mastryukova, T. A., Tetrahedron Letters,2006, 47, 7645-7648[5] Amigues,E. J., Hardacre, C., Keane, G., Migaud, M. E., Norman, S E., Pitner, W.R., Green Chem. 2009,11, 1391-1396

P15

NOVEL SYNTHETIC GLYCOPORPHYRINS FOR USE ASPHOTODYNAMIC THERAPY AGENTS

Robin Daly and Eoin M. Scanlan*School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland


Photodynamic therapy (PDT) agents1 are a class of molecules which induce light activatedtoxicity. These agents have significant potential for use in chemotherapy, anti-bacterial andanti-viral treatments. The benefits of these compounds include the selective activation of anotherwise non toxic drug. Light can be targeted to specific areas for example tumor tissue andcan induce excitation of the photosensitizer. The molecule can then relax either non-radiatively, radiatively or through the excitation of triplet oxygen O3 to its excited singlet stateO1. Singlet oxygen induces apoptosis in the cells where it is formed and this gives thecompound it’s therapeutic activity. The major drawbacks of these compounds havehistorically been poor site specificity, low solubility, post treatment photosensitization andlow light absorption at activating wavelengths. Chemically modifying the existingphotosensitizers with carbohydrates could provide a solution to many of these problems andexpand the use of PDT’s reagents as therapeutics.

This project focuses on the conjugation of biologically relevant carbohydrates to a PDTscaffold2. Certain tumor3 and bacterial4 cell lines over express carbohydrate recognizingproteins called lectins. These lectins could be used as a method of selectively targetingglycoporphyrins to the relevant cells with suitable carbohydrates, thereby increasing sitespecificity. The carbohydrates being highly hydrophilic molecules result in vastly improvedwater solubility. The increased polarity of these compounds may allow faster removal fromthe body hence lowering post treatment photosensitization. Presented is a summary of thework to date on the synthesis and biological evaluation of this novel class of compounds.

1 Q. Peng, J. Natl. Cancer Inst. 1998, 90, 889.2 E. M. Scanlan, Eur. J. Org. Chem. 2010, 1026.3 Zhu et al. BMC Cancer 2010, 10:290.4 R. Roy, Chem. Med. Chem. 2007, 2, 1190.

P16

SYNTHESIS OF ORTHOGONALLY PROTECTEDLIPOPOLYSACCHARIDE STRUCTURES FROM NEISSERIA

MENINGITIDIS

Katalin Daragics and Stefan OscarsonCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,


e-mail: [email protected], [email protected]

Neisseria meningitidis is the major cause of bacterial meningitis, and mainly fiveserogroups (A, B, C, W and Y-135) are associated with meningococcal meningitis. All thedifferent serogroups of N. meningitidis contain the same LPS-structures, which lacks thepolysaccharide O-antigen, thus, contain only the core and the Lipid A part. The structure ofthe conserved inner core part has been identified (Fig. 1) [1]. In our ongoing programme weaim to synthesize a glycoconjugate vaccine against N. meningitidis based on LPS structures.

-D-Glcp -D-KdopPEtN 1 2

3 or 6 4 4

-D-GlcNAcp-(12)-L--D-Hepp-(13)-L--D-Hepp-(15)--D-Kdop-(26)-LipidA

Figure 1. Structure of the conserved inner core of N. meningitidis LPS.

We now report on the preparation of the heptose-containing trisaccharides (I)containing orthogonal protecting groups at positions O-2, O-3 and O-6 of the second heptoseresidue. This trisaccharide precursor (I) can be used for both N. meningitidis and H.influenzae structures. We present efforts towards glycosylation of the orthogonally protectedacceptors using different N-acetyl glucosamine units to afford the tetrasaccharide donors (II).

O OOH

HOHOO

OOH

OH

HOHO

O

OR5OHO

HOR6O

O

OHOHO

O

O

NH

OHO

HO

COOH

OMe

ProteinHN

O

OBzO

O

OOBn

OR3

OR2O

BnO

BzOR1O

O

OBz

OBzBzO

BzO

O OOBn

BzOAcOO

OSMe

OBz

OBz

BzOBzO

OR4O

R2OBnO

BzOR1O

n

R

O

AcHN

HOHO

HO

R1, R2, R3: orthogonal protecting groupsR5, R6: phosphoethanolamine and/or H

R4: D-GlcNAcp Neisseria meningitidisor L,D-Hepp H. influenzae

I. II.

Figure 2. Structures of the orthogonally protected trisaccharide precursors and tetrasaccharidedonors

References:[1] Cox, A. D.; Wright, J. C.; Gidney, M. A. J.; Lacelle, S.; Plested, J. S.; Martin, A.; Moxon, E.; Richards,

J. C. Eur. J. Chem. 2003, 270, 1759-1766.

P17

Novel Achiral Indole-Substituted Titanocenes: Synthesis and Preliminary

Cytotoxicity Studies

Anthony Deally, Helge Müller-Bunz, Donal F. O’Shea and Matthias TackeUCD Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical

Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4


Ever since the discovery of cisplatin for the treatment of a variety of tumours, there has been an

increased effort devoted to the identification and clinical development of novel organometallic

compounds which overcome cross resistance in patients and have more favourable toxicity profiles

[1]. Despite this effort, movement of other transition-metal antitumor agents toward the clinic has been

extremely slow. This is perhaps due to the assumption that organometallic chemistry and biology are

mutually incompatible with many organometallic compounds being sensitive to water and oxidation.

Research over the last decade by Alberto [2] and Jaouen [3] has shown that organometallic

pharmaceuticals can in fact be formulated.

More recently, novel methods starting from fulvenes [4] allow direct access to anti-

proliferative titanocenes via hydridolithiation of fulvenes followed by transmetallation with titanium

tetrachloride. Using this approach we have synthesised a series of eight new indole substituted

titanocene dichloride derivatives. The compounds were tested for their in vitro cytotoxicity against the

human kidney cancer cell line CAKI-1 and their results are compared with previously synthesised

structural analogues [5]. These complexes were further tested on this cell line using the co-solvent

Soluphor P, which has been shown to improve both solubility and cytotoxicity of similar complexes

[6].

TiClCl

O

O

TiClCl

N

N

TiClCl

N

N H

N

N H

Cl

Cl

[1] Y. K. Yan, M. Melchart, A. Habtemariam, P. J. Sadler, Chem. Commun., 2005, 4764.

[2] R. Alberto, R. Schibli, U. Abram, A. P. Schubiger, Coord. Chem. Rev., 1999, 190–192, 901-919.

[3] F. Le Bideau, M. Salmain, S. Top, G. Jaouen, Chem. Eur. J., 2001, 7, 2289-2294.

[4] A. Deally, J. Claffey, B. Gleeson, M. Hogan, H. Müller-Bunz, S. Patil, D. F. O’Shea, M. Tacke, Polyhedron, 2010, 29,2445-2453.[5] A. Deally, B. Gleeson, H. Müller-Bunz, S. Patil, D. F. O’Shea, M. Tacke, J. Organomet. Chem., (in print)[6] P. Parijat Jain, S.H. Yalkowsky, Int. J. Pharmaceutics, 2007, 342, 1-5.

P18

Design and synthesis of novel compounds as potential therapeutics for

Type-II Diabetes Mellitus.

Robert W. Devine1, John C. Stephens1, Trinidad Velasco-Torrijos1, Gemma K. Kinsella2, Jose A. C.

Sandoval2, Clara Redondo2, and John B.C. Findlay2

1Chemistry Department NUI Maynooth, Ireland, 2Biology Department NUI Maynooth, Ireland,

Type-II diabetes is a global epidemic with 285 million cases reported worldwide and it is estimated

that this will further increase to 438 million cases by the year 20301. Current treatments include weight

loss, exercise and drugs such as Rosiglitazone, Tolazamide and Metformin which have associated side

effects2a.b.c. A novel pathway for the control and treatment of Type-II diabetes involves a member of

the lipocalin family of proteins known as Retinol Binding Protein 4 (RBP4) (Figure 1).

Figure 1: holoRBP4

RBP4 is the main transporter of retinol (Vitamin A) throughout the body, where retinol is

accommodated in the β-barrel. Binding of retinol has shown to increase the lipocalin’s binding affinity

for the protein Transthyretin (TTR), preventing glomerular filtration of RBP43. As individuals with

insulin resistance exhibit increased levels of serum RBP43, current work is aimed at decreasing the

levels of serum RBP4 by destabilizing the RBP4-TTR interaction, thus causing renal filtration.

Molecular modeling of RBP4 and subsequent in silico docking studies has allowed for the selection,

synthesis and testing of ligands, in vitro and in vivo, which are capable of competing with retinol for

binding in the β-barrel causing subsequent destabilization of the RBP4-TTR interaction.

1. Nigel Unwin (co-chair), Delice Gan (co-chair), Jean Claude Mbanya, Ambady Ramachandran, Gojka Roglic, Jonathan Shaw, Gyula Soltèsz, David Whiting,

Janice Zgibor, Ping Zhang, Paul Zimmet, Diabetes Atlas, 2010.

2. a. Pan, H.-J.; Lin, Y.; Chen, Y. E.; Vance, D. E.; Leiter, E. H., Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes:

Relation to dysregulated phosphatidylcholine metabolism. Vascular Pharmacology 2006, 45 (1), 65-71, b. Schmitt, J.; Johns, S., Altering therapy of Type-II diabetes-

Mellitus from insulin to Tolazamide increases blood-pressure in spite of weigth-loss. American Journal of Hypertension 1995, 520-523, c. Salpeter, S.; Greyber, E.;

Pasternak, G.; Salpeter, E., Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Datatbase of Systematic Reviews 2010

3. Yang, Q.; Graham, T.; Mody, N.; Preitner, F.; Peroni, O.; Zabolotny, J.; Kotani, K.; Quadro, L.; Kahn, B., Serum retinol binding protein 4 contributes to insulin

resistance in obesity and type 2 diabetes. NATURE 2005, 356-362.

P19

CATALYTIC ENANTIOSELECTIVE 3+2 CYCLOADDITION OFISOCYANIDE ESTERS TO 4-NITRO-5-STYRYLISOXAZOLES

Mauro F. A. Adamo, Paolo Disetti and Surisetti Suresh


Dublin.


4-Nitro-5-styrylisoxazoles 1 emerged as optimal Michael acceptors in chiral settingsemploying chiral phase transfer catalysis.1 Herein we present an extension of this study inwhich title compounds 1 were used for the development of a new organocatalytic 3+2cycloaddition reaction. Hence compounds 1 were reacted with isocyanide esters 2 in thepresence of a chiral phase catalyst 3 to obtain desired dihydropyrrolidines 4 in high yield,high de and in 87-97% ee. The dihydropyrrolidines 4 were converted in two steps to 2,3,4-trisubstituted pyrrolidines.

R

NO

MeNO2 EtO

NC

O

cat. 3 (10%)K3PO4 (5 equiv.)toluene, 0 °C

N

HONH

MeO

Br

tBu

31 2

4

tBu

NH

NO

NO2

CO2EtR1

NH

NO

NO2

CO2EtR1

Et3SiH

-78 °C

5

NH

NO

NO2

CO2EtR1

1.KMnO4 3 equivDioxane/Water 0 °C2. TMSCHN2

6

NHMeO2C

CO2EtR1

a) 12 examples(b) both enantiomers(c) yields 85-90%(d) ee 87-97%(e) dr 10:14

References:

[1] A. Baschieri, L. Bernardi, A. Ricci, S. Suresh, M. F. A. Adamo, Angew. Chem. Int. Ed. 2009, 48, 9342.

(a)

(c)

(b)

P20

The Synthesis of Quinine-based, Quinolone and Organotin compounds andtheir evaluation against Gram-positive and Gram-negative bacteria.

N. A. Dolan,1 Declan Gavin,1 Daniel Hurley,1 K. Kavanagh,2 J. McGinley1

and J. C. Stephens.11Department of Chemistry, National University of Ireland Maynooth, Co. Kildare, Ireland,

2Department of Biology, National University of Ireland Maynooth, Co. Kildare, IrelandEmail: [email protected]

Our current work focuses on the synthesis of a family of quinine-based, quinolone, andorganotin compounds, Figure 1, and their biological evaluation against the gram positive andgram negative bacteria Staphylococcus aureus, Pseudomonas aeruginosa and E. coli.

Quinine is well known for its antimalarial properties (chloroquine).1 However, recentinvestigations into the antibacterial properties of some quinine compounds have showninhibition of S. aureus, E. coli and P. aeruginosa growth.2 Although quinines have a longhistory of medical use dating back to the 17th century, quinolones were first discovered as aby product of chloroquine production in the early 20th century.3

Quinolones are broad spectrum antibacterials that work by inhibiting bacterial DNAreplication by forming complexes with one of two bacterial enzymes; (1) DNA gyrase or (2)DNA topoisomerase IV.4 Quinolone molecules show a 1000-fold selectivity for bacterialtopoisomerase over the human topoisomerase enzyme, making them very attractiveantimicrobial agents.1

We are also interested in the antibacterial properties of organotin complexes. Organotincomplexes were first reported in 1849 and have a wide range of biological applications,including fungicides and bactericides.5

Figure 1. Generic structures of (a) quinolone, (b) quinine and (c) organotin complex,R=site of substituent variation, L= Ligand.

References:1. Patrick G. L. An Introduction to medicinal chemistry 3rd Edn, 20052. Kharal S. A.; Hussain Q.; Ali S.; Fakhuruddin. Quinine is bactericidal. J Pak Med Assoc. 2009, 4, 208-

2113. Rádl S. From Chloroquine to Antineoplastic Drugs? The Story of Antibacterial Quinolones. Archiv der

Pharmazie. 1996, 3, 115-119.4. Drlica K.; Malik M. Fluoroquinolones: Action and Resistance. Current Topics in Medicinal Chemistry

2003, 3, 249-2825. Davies A. G.;Gielen M.; Pannell K. H.; Tiekink E. R. T. Tin Chemistry Fundamentals, Frontiers, and

Applications. 2008

P21

STEREOSELECTIVE SYNTHESIS AND ENZYMATIC REFINEMENTOF P-STEREOGENIC PHOSPHONAMIDATE PROTIDE DRUG

PRECURSORS

Jens O. Thomann, Andrew N. Bigley, Frank M. Raushel, Katherine S. Dunne and Declan G.Gilheany*

Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,University College Dublin, Belfield, Dublin 4, Ireland

E-mail: [email protected], [email protected], [email protected]

Nucleosides are an important drug class that includes some well-known drugs such as Zovirax(cold sores), AZT (HIV) and Gemzar (anti-cancer). To be effective, such drugs requireactivation within the target cells of the body. However, this activation often is not veryefficient and the therapeutic potential for the nucleoside is limited (or removed). So drugcandidates that might otherwise be very effective could be missed. The newly emerging classof "ProTide" nucleoside drugs[1] carry an extra P-stereogenic phosphorus-containing piece,which enables their self-activation.

The development of synthetic strategies for ProTide drugs has been limited due to difficultiesin synthesising the P-stereogenic portion with high stereoselectivity.

We present two different stereoselective synthetic strategies that result in selectivities of up to95% d.e.: Route A uses a chiral auxiliary strategy in the presence of N-methylimidazole(NMI)[2] and Route B is based on the stereoselective oxidation of phosphonamidites underasymmetric Appel conditions.[3]

Further, we present initial results of a new enzymatic purification strategy using aphosphotriesterase (PTE) mutant.

Pamino acid

O

X

Pproline ester

Cl

X

O

Pamino acid

O

O

asymmetricAppel reaction

NN

up to 95% d.e.

PTE100% d.e.

amino acid = proline or alanine esters, X = functionality suitable for coupling reactions

?

References:

[1] C. Schultz, Bioorg. Med. Chem. 2003, 11, 885.[2] J. F. Cavalier, F. Fotiadu, R. Verger, G. Buono, Synlett 1998, 1, 73.[3] E. Bergin, C. T. O’Connor, S. B. Robinson, E. M. McGarrigle, C. P. O’Mahony, D. G. Gilheany, J. Am.

Chem. Soc. 2007, 129, 9566.

P22

1,3-DIPOLAR CYCLOADDITION OF SILYL NITRONATES TO MESO-TETRAARYL PORPHYRINS

Mothi M. Ebrahim and Mathias O. Senge*SFI Tetrapyrrole Laboratory, School of Chemistry, Trinity College Dublin, Dublin 2, Ireland


The ever expanding applications of porphyrins require development of new synthetic routes inorder to access novel materials. Apart from total synthesis, chemical modification of simple,easily available porphyrins offers a complimentary and perhaps more wide-ranging approachto obtain such molecules.[1] In this context it is well known that the peripheral double bondsof the porphyrin macrocyle are partially isolated from the macrocyclic conjugation pathway.The participation of these double bonds in concerted Diels-Alder reactions and 1,3-dipolarcycloadditions has been demonstrated as an expedient route to the highly desirable chlorins.[2]

Silyl nitronates are a class of 1,3-dipoles that can be considered as synthetic equivalents ofnitrile oxides in their reaction with olefins since the resulting N-siloxyisoxazolidines can bereadily transformed to isoxazolines.[3] Here, we will present the results of our exploration ofreactivity of silyl nitronates towards electron deficient porphyrins.Triisopropylsilylalkylideneazinates react with meso-tetrakis(pentafluorophenyl)porphyrin in1,3-dipolar cycloadditions to yield novel isoxazole-fused chlorins.

References:

[1] M. O. Senge, Acc. Chem. Res. 2005, 38, 733.[2] A. C. Tome, M. G. P. M. S. Neves, J. A. S. Cavaleiro, J. Porphyrins Phthalocyanins 2009, 13, 408.[3] I. N. N. Namboothiri, N. Rastogi, Top. Heterocycl. Chem. 2008, 12, 1.

P23

Design of chromene based compounds with affinity for steroid hormonereceptors

Bill C. Egan, Mary J. Meegan*School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, D2, Ireland

Email: [email protected], [email protected] cancer is the second most common cancer in Ireland and accounts for 28% of all

cancers in women in Ireland, with an average of 1726 new diagnosis each year.1

Tamoxifen is a selective estrogen receptor modulator (SERM) with a triarylethylenestructure which acts as an estrogen antagonist in the breast. This drug is used extensively asan endocrine treatment for breast cancer; however, due to its flexible structure it can also actas an agonist in endometrial tissue resulting in unwanted side effects including endometrialcancer. Many modified SERMs have been developed based on non-isomerisable scaffoldstructures. Recently, through in silico HTS methods, we have developed a novel series ofestrogen receptor modulators which bind to the receptor with a considerably higher potencythan tamoxifen, while also inhibiting the proliferation of a human MCF-7 breast carcinomacell line2. These novel structures are designed to incorporate the potent chromene scaffoldstructure (fig. 1).

O NH2

OR2

O

O

R3

Fig.1: Chromene Scaffold Structure

R1

A series of chromene compounds were synthesised by reaction of different benzaldehydes,resorcinol and ethyl cyanoacetate in base piperidine. Yields were in the range 50-70%. Alibrary of 45 compounds was produced with variation of substituents on C-4 aryl ring. Acomprehensive series of ester derivatives, 19 to date, were obtained by reaction of chromenephenolic group with appropriate acid chlorides. The novel compounds were characterised by1H and 13C NMR, IR, and HRMS. A novel Pyrano[3,2-g]chromene product was obtained andcharacterised by single crystal X-ray analysis. Chromene products are to be evaluated forcytotoxicity in MCF-7 cells and also for ER binding activity.

The molecular modelling study of the products has been carried out to determine the three-dimensional topography and minimised energy structural characteristics of the chromenecompounds. With the availability of several structures of the ligand binding domain of ERand ER, it is possible to perform various in silico docking studies of the newly synthesisedcompounds at the proposed binding site which allow for optimisation of the molecular designi.e. positioning of the aryl rings on the chromene heterocycle and nature of the arylsubstituents to obtain maximum cellular cytotoxic effects.

References:1. www.breastcancerireland.com/2. Knox, A. J.; Meegan, M. J.; Sobolev, V.; Frost, D.; Zisterer, D. M.; Williams, D. C.; Lloyd, D.

G. Target specific virtual screening: optimization of an estrogen receptor screening platform. JMed Chem 2007, 50, 5301-10

Quaternarized pdppz: Synthesis, DNAa Novel dppz Derivative That Causes Cellular Death Upon Light

Robert B. P. Elmes,a Marialuisa Erby,D. Clive Williams

a School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin,

b School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.c School of Chemistry and Chemical Biology, Centre for Chemical Synthesis and Chemical

Biology, University College Dublin, Belfield, Dublin 4, Ireland

email:

The development of novel low molecular weight cancer therapeuticsarea of research for many years. Such molecules should ideally possess good water solubility,rapid cellular uptake, undergo selective localisation and be able to induce programmed celldeath of cancer cells.[1]

Moreover, the ability to prepare molecules that selectively bind DNA, and that exhibitphotophysical properties that are sensitive to the binding event, continues to be the focus of asignificant amount of research.[2]

nucleic acid probes, whose potential applications as highly sensitive diagnostic agents arevast.[3] In addition, species that display inherent excited state reactivity with DNA representan important step in alternative approaches to Photodynamic Therap

Herein, we present the synthesis of a novel quaternarized polypyridyl moleculepyrazino[2,3-h]dipyrido[3,2-a:2’,3’combining, in a single structure, two wellphenazine (dppz) and 1,4,5,8-tetraazaphenanthrene (TAP), that are commonly used as DNAbinding ligands in Ru(II)polypyridyl complexes.quaternarized pdppz derivative to bind to DNA by showing concomitant changes in its groundand excited state photophysical properties. Furthermore, the compound was also shown todisplay rapid cellular uptake, and icell lines.

References:[1] P. B. Dervan, A. T. Poulin-Kerstien, E. J. Fechter, B. S. Edelson,[2] M. J. Hannon, Chem. Soc. Rev.[3] K. E. Erkkila, D. T. Odom; J. K. Barton,[4] I. Ortmans, B. Elias, J. M. Kelly, C. Moucheron, A. Kirsch

Quaternarized pdppz: Synthesis, DNA-Binding and Biological Studies ofa Novel dppz Derivative That Causes Cellular Death Upon Light

Irradiation

Marialuisa Erby,b Suzanne M. Cloonan,b Susan J. Quinn,Clive Williams*b and Thorfinnur Gunnlaugsson*a

School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin,Dublin 2, Ireland.

School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.School of Chemistry and Chemical Biology, Centre for Chemical Synthesis and Chemical



The development of novel low molecular weight cancer therapeutics has been a highly topicalarea of research for many years. Such molecules should ideally possess good water solubility,rapid cellular uptake, undergo selective localisation and be able to induce programmed cell

ability to prepare molecules that selectively bind DNA, and that exhibitphotophysical properties that are sensitive to the binding event, continues to be the focus of a

[2] Such species have become highly desirable for use anucleic acid probes, whose potential applications as highly sensitive diagnostic agents are

In addition, species that display inherent excited state reactivity with DNA representan important step in alternative approaches to Photodynamic Therapy (PDT).

Herein, we present the synthesis of a novel quaternarized polypyridyl moleculea:2’,3’-c]phenazine, or pdppz. This new species is based on

combining, in a single structure, two well-known polypyridyl ligands, dipyrido[3,2tetraazaphenanthrene (TAP), that are commonly used as DNA

binding ligands in Ru(II)polypyridyl complexes.[4] We have investigated the ability of thequaternarized pdppz derivative to bind to DNA by showing concomitant changes in its groundand excited state photophysical properties. Furthermore, the compound was also shown todisplay rapid cellular uptake, and induced apoptosis upon light irradiation in various cancer

Kerstien, E. J. Fechter, B. S. Edelson, Top. Curr. Chem.,Chem. Soc. Rev. 2007, 36, 280.

K. E. Erkkila, D. T. Odom; J. K. Barton, Chem. Rev. 1999, 99, 2777.I. Ortmans, B. Elias, J. M. Kelly, C. Moucheron, A. Kirsch-De Mesmaeker, Dalton Trans

P24Binding and Biological Studies of

a Novel dppz Derivative That Causes Cellular Death Upon Light

Susan J. Quinn,c

School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin,

School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.School of Chemistry and Chemical Biology, Centre for Chemical Synthesis and Chemical


has been a highly topicalarea of research for many years. Such molecules should ideally possess good water solubility,rapid cellular uptake, undergo selective localisation and be able to induce programmed cell

ability to prepare molecules that selectively bind DNA, and that exhibitphotophysical properties that are sensitive to the binding event, continues to be the focus of a

Such species have become highly desirable for use asnucleic acid probes, whose potential applications as highly sensitive diagnostic agents are

In addition, species that display inherent excited state reactivity with DNA represent

Herein, we present the synthesis of a novel quaternarized polypyridyl moleculec]phenazine, or pdppz. This new species is based on

dipyrido[3,2-a:2’,3’-c]tetraazaphenanthrene (TAP), that are commonly used as DNA

We have investigated the ability of thequaternarized pdppz derivative to bind to DNA by showing concomitant changes in its groundand excited state photophysical properties. Furthermore, the compound was also shown to

nduced apoptosis upon light irradiation in various cancer

., 2005, 31.

Dalton Trans., 2004, 668.

P25

Synthesis of the Lewisb family pentasaccharide

Viviane Fournière1*, Linnéa Skantz2, Stefan Oscarson2,3, MartinaLahmann1,2

1Bangor University, Bangor, Gwynedd, LL57 2UW, UK, 2Arrhenius Laboratoriet, StockholmUniversity, 10691 Stockholm, Sweden, 3CSCB, University College Dublin, Belfield, Dublin 4,

Ireland


Helicobacter pylori is a human pathogenic bacterium and a causative agent of gastricinflammations leading to peptic ulcers and gastric cancers [1]. H. pylori binds to the host cellsvia an outer-membrane protein, the blood group antigen binding adhesin (BabA) [2]. Thislectin adheres to carbohydrate structures situated on the gastric epithelial cells. The principalligands are the Lewisb (Leb) blood group antigen and related structures [3]. Lebhexasaccharide conjugates are so far the best ligands for the BabA. The conjugatedtetrasaccharide is a poor ligand, while the free tetrasaccharide inhibits the binding. Thepentasaccharide has been synthesised to investigate the minimal epitope required for efficientbinding to H. pylori and to study the influence of distance and spacer properties.Despite its similarity to the previously prepared Leb tetra- and hexasaccharides, this synthesisrevealed some unexpected synthetic challenges already on the monosaccharide level.Eventually, the introduction and regioselective opening of an 3,4-benzylidene acetal, anastonishingly rarely used sequence, produced the required azidopropyl galactosyl acceptor,providing a reliable and easy route to the target pentasaccharide 1.

References:

[1] T.L. Cover, D.E. Berg, M.J. Blaser, and H.L.T. Mobley, Principles of bacterial pathogenesis, Ed. E. A.Groisman (Acadamic Press, CA, US) (2001).

[2] Ilver, D., A. Arnqvist, J. Ögren, I.-M. Frick, D. Kersulyte, E.T. Incecik, D.E. Berg, A. Covacci, L.Engstrand, and T. Borén, Science, 279, 373 (1998).

[3] Marina Aspholm-Hurtig, Giedrius Dailide, Martina Lahmann, Awdhesh Kalia, Dag Ilver, NiamhRoche, Susanne Vikström, Rolf Sjöström, Sara Lindén, Anna Bäckström, Carina Lundberg, AnnaArnqvist, Jafar Mahdavi, Ulf J. Nilsson, Billie Velapatiño, Robert H. Gilman, Markus Gerhard, TeresaAlarcon, Manuel López-Brea, Teruko Nakazawa, James G. Fox, Pelayo Correa, Maria GloriaDominguez-Bello, Guillermo I. Perez-Perez, Martin J. Blaser, Staffan Normark, Ingemar Carlstedt,Stefan Oscarson, Susann Teneberg, Douglas E. Berg, and Thomas Borén, , Science, 305, 519 (2004).

P26

THE SYNTHESIS AND EVALUATION OF DNA TARGETING HYBRIDDRUGS AS NEW ANTITUMOUR AGENTS

Sandra Gannona and Sarah L. Raweb

aFOCAS Institute, Dublin Institute of Technology, Camden Row, Dublin 8, IrelandbSchool of Chemical and Pharmaceutical Sciences, Dublin Institute of Technology, Kevin

Street, Dublin 8, Ireland


Cancer affects 1 in 3 people in Ireland, and there is a continuous need for more effective anticancer treatments. Our research aims to create a new hybrid drug in which two distinctchemical entities are covalently linked together. The hybrid approach aims to optimisetherapeutic benefits of treatment while minimising side effects and avoiding the developmentof drug resistance, a common problem in many areas of medicine.The synthetic targets of this study are peroxide-containing moieties covalently linked to aDNA targeting agents including intercalators via various chains. Synthesis of the twobuilding blocks for the hybrids is well underway and suitable DNA intercalators have beenprepared by microwave and conventional synthesis. Naturally occurring endoperoxides areavailable, such as artemisinin (a 1,2,4-trioxane) and its derivatives, and have potentantimalarial activity and good antitumour activity. However, they are prohibitively expensiveand therefore synthetic endoperoxides are more attractive for this work, To date, a numberof 1,2,4-trioxolanes have been prepared.Convergent synthesis of the intercalators and endoperoxide building blocks will allow us toprepare a small library of related compounds. Varying the substitution of these buildingblocks, the chain length and the functionality of the linker will allow us to examine the effectof these structural changes on the antitumour activity, DNA affinity and to enhance the drug-like properties. A library of DNA-targeting hybrid drugs is currently being prepared.Following the preparation of the hybrids we shall begin biological evaluation in tumour andnon-tumour cell lines and shall be assessing their DNA affinity.

P27

CYCLIC SULFONAMIDES: THEIR REGIOSELECTIVE FORMATIONAND SYNTHETIC APPLICATIONS

Paul Evans*, Johannes E. M. N. Klein and Kimberly GeogheganCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



We have shown that the sulfonyl group present in cyclic sulfonamides may be efficientlyexcised under reductive conditions, whereby, both the N-S and the C-S bonds are reduced (eg.“double reduction” 2 to 3).[1] The cyclic sulfonamide starting materials for this process areconveniently accessed by a palladium mediated intramolecular Heck reaction, followed byalkene hydrogenation (eg. 1 to 2).[2] In relation to the Heck reaction we have uncovered aninteresting regioselectivity. Namely, that unsymmetrical trisubstituted alkenes favour C-Cbond formation at the most substituted carbon atom, thereby, generating a quaternary all-carbon stereogenic centre. This selectivity and the double sulfonamide reduction has beenapplied in a short synthesis of the amaryllidaceae alkaloid mesembrane 4.[3]

N

R

SO2

Br

SO2

N

R

NH

PhR

NMeH

OMe

OMe

1: R = Me, Ph 2: R = Me, Ph

(1) Heck;

(2) H2

(1) Li, NH3;

(2) work-up

3: R = Me, Ph Mesembrane (4)

References:

[1] For example see: P. Evans, T. McCabe, B. Morgan, S. Reau, Org. Lett. 2005, 7, 43[2] For a review see: J. T. Link, Org. React. 2002, 60, 157.[3] J. E. M. N. Klein, K. Geoghegan, N. Méral, P. Evans, Chem. Commun. 2010, 46, 937.

P28

SYNTHESIS OF MONODEOXY TRISACCHARIDES RECOGNISED BYCALRETICULIN/CALNEXIN

Stefan Oscarson and Anja Glinschert

Centre for Synthesis and Chemical Biology,UCD, Belfield, Dublin 4, Ireland


Interaction studies between the lectins Calreticulin/Calnexin and the high-mannose-typeglycan Glc1Man9(GlcNAc)2 are of immense biological interest.[1] The whole folding processof all N-glycoproteins depends on this recognition process.[2]

We reported earlier the synthesis of the trisaccharide α-D-Glcp-(1→3)-α-D-Manp-(1→2)-α-D-ManpOMe, part of the Glc1Man9(GlcNAc)2,[3] which is of special interest as it shows a strongbinding affinity toward Calreticulin in isothermal titration calorimetry (ITC) studies.[4] Toinvestigate in further details binding interactions with Calreticulin, a series of deoxyanalogues has been synthesised in our group.[5]

We now prepared the four monodeoxy analogues (1-4) of the above mentioned trisaccharideswhose synthesis is presented.

O

OO

OO

HOHO

R1

HOHO

OMe

HOR4

HO

R3

R2

1 R1 = H, R2 = OH, R3 = OH, R4 = OH2 R1 = OH, R2 = H, R3 = OH, R4 = OH3 R1 = OH, R2 = OH, R3 = H, R4 = OH4 R1 = OH, R2 = OH, R3 = OH, R4 = H

We planned and carried out a synthetic pathway in which the deoxy functions were alreadyintroduced at the monosaccharide level. The trisaccharides have been synthesised using alinear approach utilizing monosaccharide thioglycoside donors.

References:

[1] Peterson, J. R.; Ora, A.; van Nguyren, P.; Helenius, A. Mol. Biol. Cell., 1995, 6, 1173-1184[2] Rodan, A. R.; Simons, J. F.; Trombetta, E. S.: Helenius, A. EMBO J. 1996, 15, 6921-6930[3] Gemma, E.; Lahmann, M.; Oscarson, S. Carbohydr. Res., 2005, 340, 2558-2562[4] Kapoor, M; Sinivas, H.; Eaazhisai, K.; Gemma, E.; Ellgaard, L.; Oscarson, S.; Helenius, A.; Surolia, A., J.Biol. Chem., 2003, 278, 6194-6200[5] Gemma, E.; Lahmann, M.; Oscarson, S. Carbohydr. Res., 2006, 341, 1533-1542

P29

NOVEL PLATINUM DRUG CANDIDATE WITH DUAL DNA BINDING

AND HISTONE DEACETYLASE INHIBITORY ACTIVITY

Darren Griffith,a Maria Morganb, Celine J. Marmiona

aCentre for Synthesis & Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry,

Royal College of Surgeons in Ireland, Dublin 2, Ireland ([email protected])bMolecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland

Metal complexes are attractive for drug design[1] and over the past 30 years Pt

compounds have played a very important role in treating cancer.[2] The cytotoxicity of

platinum drugs, e.g. cisplatin, is attributed to their ability to form DNA adducts and ultimately

induce apoptosis. The application and efficacy of platinum drugs is limited by drawbacks

though such as limited activity against certain cancers, resistance and dose-related toxicity.[2]

There is therefore an urgent need to develop novel and innovative therapeutic strategies for

combating cancer.

Consequently, we have developed a novel platinum drug candidate as a potential

alternative treatment for cancer. This drug candidate should have a mechanism of action

different to classical Pt drugs. The rationale behind the development of our drug candidate, its

synthesis and its pharmacological results obtained to date will be provided.[3]

References

[1] P. C. A. Bruijnincx, P. J. Sadler, Curr. Opin. Chem. Biol. 2008, 12, 197-206.[2] N. J. Wheate, S. Walker, G.E. Craig, R. Oun, Dalton Trans. 2010, 39, 8113-8127.[3] D. Griffith, M. P. Morgan, C. J. Marmion, Chem. Commun., 2009, 6735-6737.

This research was supported by Science Foundation Ireland under Grants No. [07/RFP/CHEF570] and[08/RFP/CHE1675]. We also gratefully acknowledge the Programme for Research in Third Level Institutions(PRTLI), administered by the HEA for funding.

P30

Stereoselective Synthesis and Biological Evaluation ofNovel Aromatic Lipoxin A4 Analogues

Gavin Haberlin, Colm Duffy, Syed Tasadaque A. Shah, Surendra Singh, Timothy P.O'Sullivan, Catherine Godson and Patrick J. Guiry*

Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular andBiomedical Research, School of Chemistry and Chemical Biology, University College

Dublin, Belfield, Dublin 4, Ireland

email:[email protected]

Lipoxins (LX) are bioactive eicosanoids that activate human monocytes, inhibit neutrophilsand serve as regulators of inflammation.1 Native lipoxins LXA4 and LXB4 demonstrate potentanti-inflammatory and pro-resolution bioactins. However, LXA4 is rapidly regulated byconversion to inactive LX metabolites via local metabolism that involves dehydrogenation asthe predominant route. Recently, we have demonstrated the bioactivity of chemically stablearomatic LXA4 and LXB4 analogues.2 These aromatic analogues were found to result in asignificant increase of phagocytosis of apoptotic polymorphonuclear leukocytes, comparableto the effect of native LXA4. A goal of this project is to synthesise substituted aromatic ringanalogues of LXA4 to facilitate structure activity relationship studies. Here, we report on thestereoselective synthesis of new aromatic LXA4 analogues. The Sharpless asymmetricepoxidation, various protection/deprotection steps, an asymmetric reduction of an alkyl arylketone, a novel one-pot ZrCl4 esterification/deprotection3 and a Pd-catalysed Heck reactionwill be discussed.

OH

OH

HO OH O

LXA4

References:[1]. Serhan, C. N.; Hamberg, M.; Samuelsson, B. Biochem. Biophys. Res. Commun. 1984, 118, 943-949.[2]. O’Sullivan, T. P.; Vallin, K. S. A.; Shah, S. T. A.; Fakhry, J.; Maderna, P.; Scannell, M.; Sampaio, A. L.

F.; Perretti, M.; Godson, C.; Guiry, P. J. J. Med. Chem. 2007, 50, 5894.[3]. Singh, S.; Duffy, C.; Tasadaque, S.; Guiry, P. J. Org. Chem. 2008, 73 (16), 6429-6432

P31

Towards the Development of Antitubercular Drugs: Synthesis of Analoguesof Mycothiol

Brian Higgins, Stefan OscarsonSchool of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4,

Ireland


Mycothiol (1, Fig.1) is a pseudodisaccharide which is the putative defence of the gram-positive Actinomycetales bacteria against xenobiotics and oxidative stress. This group ofbacteria includes the pathogen, Mycobacterium tuberculosis which causes tuberculosis. [1] Ithas been suggested that due to the increased sensitivity of mycothiol-deficient mutants toelectrophiles, free radicals and antibiotics, the enzymes involved in the biosynthesis ofmycothiol are potential drug targets.[2] Mycothiol and analogues will shed light on theimportant interactions between the enzymes and their specific substrates thus aiding thedevelopment of anti-tubercular drugs.

The aim of this project is to synthesise stable carbohydrate based analogues of mycothiol as S-and C- glycosides that vary in the inositol moiety and at the thiol functional group. C-glycosidation via samarium diiodide reduction of mannosyl pyridylsulfone (2, Fig. 2) in thepresence of the aldehydes[3] such as 3 (Fig. 2) is presented. Methods for the regioselectiveprotection of the myo-inositol moiety and its conversion to a thio-acceptor is also described.

OH

1, MSH

OHO

HONH

OH

ONHAc

OHO

OHOH

OH

HS

Fig. 1: Mycothiol

Fig. 2: SmI2 promoted C-glycosidation towards the synthesis of a C-glycoside analogue (5) of MSH.

References:

[1] H. Spies, D. Steenkamp, European journal of biochemistry/FEBS 1994, 224, 203.[2] B. Metaferia, S. Ray, J. Smith, C. Bewley, Bioorganic & medicinal chemistry letters 2007, 17, 444.[3] O. Jarreton, T. Skrydstrup, J. Espinosa, J. Jiménez-Barbero, J. Beau, Chemistry- A European Journal 1999, 5, 430.

P32

LINEAR AND CONVERGENT SYNTHESIS OF MUCIN O-GLYCANCORE STRUCTURES FOR THE INVESTIGATION OF THEIR

BINDING TO GUT BACTERIA

Stefan Oscarson*, Martin Hollinger and Fana Abraha


email: [email protected], [email protected], [email protected]

Helicobacter pylori1 and Campylobacter jejuni2 are pathogenic species responsible for acuteand chronic infections of the human gut. We want to investigate the interaction between thesebacteria and mucin glycoproteins.

A number of mucin core structures with different aglycons have been synthesized using eithera linear or a convergent approach. These structures will be used for the design and preparationof microarrays, glycan analysis experiments and also to identify binding structure hits.

Different methodologies to create the glycosidic linkage (for example novel thioglycosidedonors) have been developed to generate the target core structures fast and efficiently.

[1] T. L. Cover, D. E. Berg, M. J. Blaser, H. L. T. Mobley, Principles of bacterial pathogenesis 2001,Ed. E. A. Groisman (Academic Press, San Diego, CA, US), 510-558[2] K. T. Young, L. M. Davis, and V. J. Dirita, Campylobacter jejuni: molecular biology andpathogenesis, Nat Rev Microbiol 2007 5 665.

P33

SYNTHESIS OF FLUORINATED OLIGOSACCHARIDES FORINTERACTION STUDIES WITH LECTINS

Stefan Oscarson and Angela S. InfantinoCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



Lectins are carbohydrate-binding proteins, without enzymatic activity and non-immuneorigin, which are present in animals and plants. In animals they are involved in a wide numberof biological events from the regulation of cell adhesion to roles in the immune system byrecognizing carbohydrates. Lectins can also be used by bacteria and virus for the adhesion andinvasion of the host cell.1

This project focus on synthesis of a library of fluorinated oligosaccharides (disaccharides andtrisaccharides) and screening their binding activity to Concavalin A (lectin extracted fromjack-beans which binds specifically mainly internal and non-reducing α-mannosyl groups) by19F-detected heteronuclear 1H→19F-STD (Saturation Transfer Difference) NMRspectroscopy.2,3

The synthesis is based on the combined use of common mannose building block derivativesas donors or acceptors.

References:

[1] H.-J. Gabius, The sugar code: Fundamentals of Glycosciences, Wiley-VCH, Weinheim 2009, 261-347.[2] M. Mayer, B. Meyer Angew. Chem. Int. Ed., 1999, 38, 1784-1788.[3] T. Diercks, J. P. Ribeiro, F. J. Canada, S. André, J. Jiménez-Barbero, H.-J. Gabius Chem. Eur. J. 2009,

15, 5666-5668 .

OR

OMe

OHO

ORHO

HOHO

O

ORHO

HOHO

R = OH or FOR

OMe

HOHO

ORHO

HOHO

O

P34

GUANIDINO PYRIDINES: COMPUTATIONAL STUDYAND SYNTHESIS

Brendan Kelly, Fernando Blanco and Isabel RozasCentre for Synthesis and Chemical Biology, School of Chemistry, Trinity College Dublin,

Dublin 2, Ireland


In a recent series of publications,[1] our group has described the design and synthesis of morethan 80 aromatic guanidine derivatives. These compounds have a wide range of applicationsthroughout the field of medicinal chemistry, including as DNA minor groove binders for thepotential treatment of cancer,[2] as α adrenoceptor ligands for the treatment of CNSdisorders,[3] and as therapeutics in many other areas.

The present study involves the design, synthesis and characterisation of a series of 2-guanidinopyridines (Fig. 1, where R= Cl, Br, H, Me, THQ; R’= R’’= Boc; R’= Boc, R’’= Pr).These molecules can adopt several conformational states depending on the nature of thesubstituents on the guanidine moiety. The preparation of these compounds is presented, aswell as the findings from a thorough study on their conformational preferences involvingspectroscopic, computational, and X-ray crystallographic techniques.

Fig. 1: The “Up” or the “Down” conformations can be adopted depending on the nature of R’ and R’’

The intramolecular hydrogen bonding (IMHB) networks present in these molecules (assuggested by the computations and confirmed by the crystallographic structures) are thedeciding factor for the conformation adopted. Thus, taking the NNN axis as reference, “Up”or “Down” conformations, as shown in Fig. 1, can be adopted depending on the nature of R’and R”, and independently of R.

With this knowledge, a better understanding of the mode of binding of these molecules tobiological receptors may be obtained, allowing for the design of more efficient ligands in thefuture.

References:

[1] F. Rodriguez, I. Rozas, J. E. Ortega, A. M. Erdozain, J. J. Meana, L. F. Callado, J. Med. Chem., 2009, 52,601-609.

[2] P. S. Nagle, F. Rodriguez, A. Kahvedzic, S. J. Quinn, I. Rozas, J. Med. Chem., 2009, 52, 7113-7121.[3] J. V. Greenhill, P. Lue, Prog. Med. Chem., 1993, 30, 203-326.

P35SYNTHESIS OF A HETERODIMER PEPTIDE TARGETING CANCER

CELLS

Marc Devocelle and Graeme KellyCentre for Synthesis and Chemical Biology, Department of Pharmaceutical and MedicinalChemistry, Royal College of Surgeons Ireland, 123 St Stephen’s green, Dublin 2, Ireland.


Peptides with anticancer activity have recently received attention as alternativechemotherapeutic agents.[1] The BH3 domain of pro-apopotic proteins has the ability to inducethe apoptotic response in cancer cells but is not able to cross the cell membrane. To enhancethe uptake of the peptide into the cell, different carriers have being added including lipids andalso Cell Penetrating Peptides.Buforin IIb is a Host Defence Peptide (HDP) that has the ability to translocate the cellmembrane but also to selectively induce mitochondria-dependant apoptosis in cancer cells. [2]

Furthermore, theses peptides are not susceptible to classical mechanisms of drug resistanceand do not easily select resistant mutants. This makes buforin an excellent candidate as acarrier for the BH3 peptide, but also as an anticancer candidate in its own right. The aim ofthis project is to develop a synthetic route to a heterodimer peptide including a BH3 andbuforin sequences (Figure 1). Both sequences were synthesised by including a cysteineresidue at their N-termini. They were assembled by Solid Phase Peptide Synthesis (SPPS)according to the Fmoc/t-Bu strategy and cross-linked in solution using 2,2’-dithiol-bis(5-nitropyridine) (DTNP) as the cross-linking reagent to favour the formation of the heterodimerover the homodimer.By conjugating the two peptides via a disulfide bond, this will allow the BH3 peptide to bereleased from the buforin sequence by exploiting the reducing conditions inside the cells, afterbuforin mediated cellular uptake. A heterodimer of a cysteine modified oligo-arginine peptideand of the BH3 sequence was also made as a negative control. Buforin can not only act as avector for the BH3 peptide but can also act additively or synergistically with the lattercandidate.

EDIIRNIARHLAQGDSMDR-NH2-AlaCysAc

S

S

RAGLRFPVGRLLRRLLRRLLR-NH2CysAc -Ala

BH3 Domian

Buforin IIb

Figure 1. Structure of the Heterodimer of BH3 and Buforin

References:1. Mader, J.S. and D.W. Hoskin, Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin

Investig Drugs, 2006. 15(8): p. 933-46.2. Takeshima, K., et al., Translocation of analogues of the antimicrobial peptides magainin and buforin across human cell

membranes. J Biol Chem, 2003. 278(2): p. 1310-5.3. Rabanal, F., et al., Use of 2,2’-dithiolbis(5-nitropyridine) for the heterodimerization of Cysteine Containing Peptides. Introduction

of the 5-nitro-2-pyridinesulfenyls group. Tetrahedron letters, 1996. 37(9), p. 1347-1350.

P36

The design and synthesis of dual-acting estrogen receptor conjugates

Patrick M. Kelly and Mary J. Meegan*

School of Pharmacy & Pharmaceutical Sciences,Centre for Synthesis and Chemical Biology,

Panoz Institute, Trinity College Dublin, Dublin 2, Ireland

E-mail address: [email protected], [email protected]

Breast cancer is the second most common cancer in Ireland after non-melanomatous skin cancer. Irishstatistics note that breast cancer accounts for 28% of all cancers in women in Ireland, with an average of1726 new diagnosis each year.[1] Tamoxifen is an antagonist of the estrogen receptor in breast tissue and istherefore used in the treatment of breast cancer. It is metabolized in the liver by the cytochrome P450 isoformCYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor thantamoxifen.[2]

The main objective of this research is to synthesise and evaluate the dual-acting estrogen-receptortargeting conjugate products. In designing an ER ligand moiety such as endoxifen into the conjugate scaffold,it is envisioned that the conjugate could target breast cancer cells that over-express ER, exerting theirantagonist effect while also acting as a carrier to selectively bring the covalently-bound cytotoxic agent to thearea of the tumour. These ER conjugates are designed to contain multiple pharmacophore elements,separated by a linker group.[3] The linker group is designed to be cleaved metabolically thus releasing theligands to interact at their specific targets.[4] This research involves synthesis and full characterisation of arange of acrylic acids which will be used to form direct amide conjugates. The acrylic acid are similar instructure to combretastatin 4A which belong to a class of stilbenoid phenols first isolated by Pettit[5] and foundto act as a potent inhibitors of tubulin polymerization and tumour cell proliferation .[5]

In the present work, the required acrylic acids were synthesised using the Perkin reaction of theappropriate benzaldehydes and phenylacetic acids. Endoxifen was obtained from the appropriate ketones viathe McMurry reaction. Coupling of the endoxifen and the acrylic acids utilizing a carbodiimide couplingreagent with HOBt as an additive affords a series of structurally diverse novel conjugated products. Allsynthesised compounds have been fully characterised using 1H & 13C NMR, IR spectroscopy and HRMS.Products are evaluated in the ER positive MCF-7 human breast cancer cell lines and also for ERα and ERβbinding affinity.

References:[1] Breast Cancer Ireland, http://www.breastcancerireland.com/index.php?page=About-Breast-Cancer-in-Ireland[accessed 22/07/2009][2] Desta Z, Ward BA, Soukhova NV, Flockhart DA. "Comprehensive evaluation of tamoxifen sequentialbiotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6". J PharmacolExp Ther. 2004, 310 (3): 1062–75[3] Morphy, R.; Rankovic, Z. Designed Multiple Ligands. An Emerging Drug Discovery Paradigm. J. Med. Chem. 2005,48, 1-21[4] Keely, N.O.; Meegan, M.J., Targeting Tumours Using Estrogen Receptor Ligand Conjugates. Current Cancer DrugTargets. 2009, 9 (3), 370-380[5] Pettit, G.R.; Singh, S.B.; Hamel, E; Lin, C.M.; Alberts, D.S.; Garcia-Kendal, D. Isolation and structure of the strong cellgrowth and tubulin inhibitor combretastatin A-4. Cellular and Molecular Life Sciences, 1989, 45 (2), 209-211

P37

DERAILMENT OF A DODECAKETIDE INTERMEDIATE FROM ANENGINEERED AMPHOTERICIN POLYKETIDE SYNTHASE

Naseem Khan and Patrick Caffrey†

School of Biomolecular and Biomedical Science, Centre for Synthesis and Chemical Biology,University College Dublin, Belfield, Dublin 4, Ireland

e-mail: [email protected]

Streptomyces nodosus produces the antifungal polyene amphotericin B. Numerousmodifications of the amphotericin polyketide synthase have yielded new analogues. Theketoreductase in module 10 (KR10) was previously inactivated in an effort to biosynthesisethe aglycone 19-dideoxy-19-oxo-amphoteronolide B 1. However, the mutant strainssynthesised a truncated dodecaketide intermediate that accumulated as the polyenyl-pyrone2.[1] Here re-sequencing revealed that polyketide synthase modules 11 to 18 remain intact.This shows that inactivation of KR10 creates a labile point in cycle 11 of the polyketidebiosynthetic pathway. Mechanisms for early chain termination are proposed.

OH

Me

Me

Me

HO

O

OH

O

Me

Module 10 Module 11

O

O

S

ACP

O

O

O

AT ATATATKS

KR

S

ACPAT

KR

ACPKS

Module 12

ACPAT

KR

ATATACPKS

OH

OH OH

OH

O OH

OMe

Me

Me

HO OH OH

OH

OH OH

OH

O

COOHO

19

Modules 13 - 18

1

2

References:

[1] B. Murphy, K. Andersen, C. Borrissow, P. Caffrey, G. Griffith, J. Hearn, O. Ibrahim, N. Khan, N.Lamburn, M., Lee, K. Pugh, B. Rawlings. Org. Biomol. Chem. 2010, 8, 3758 - 3770.

† NK received a HEA PRTLI Ph. D. studentship. PC is supported by SFI grant number 09/RFP/GEN2132.

P38

LANTHANIDE LUMINESCENT DISPLACEMENT ASSAYS:SELECTIVE SENSING OF Fe(II) USING Eu(III)–CYCLEN

COMPLEXES IN AQUEOUS SOLUTION

Oxana Kotova, Steve Comby and Thorfinnur GunnlaugssonSchool of Chemistry, Center for Synthesis and Chemical Biology, Trinity College Dublin,

Dublin 2, Ireland


It was shown that unsaturated lanthanide (Ln(III)) cyclen complexes are a well-suitedplatform for the sensing of anions in aqueous solution thanks to the displacement of metal-bound water molecules resulting in a significant enhancement (“switch on”) of the Ln-centered emission.[1] Recently, we developed a new heptadentate Eu(III) macrocyclic cyclencomplex (Eu.1) possessing an alkyl thiol group, which enables the adsorption of Eu.1 onto thegold nanoparticles as well as gold flat surface acting as phosphate and pH sensor in aqueousmedia.[2-4]

Herein we further modified thissystem to allow its applicationin lanthanide baseddisplacement assays for theselective sensing of metalcations. To the best of ourknowledge, none of the similarlanthanide based systems hasbeen exploited for the sensingof biologically relevant cations.The external antenna has beencarefully selected and the watersoluble 4,7-diphenyl-1,10-

phenanthrolinedisulfonatedisodium salt (B-Phen-2SO3Na)appeared as the perfect

candidate: (1) B-Phen-2SO3Na can form ternary complexes with Eu.1 and efficiently sensitiseLn emission; (2) the presence of the sulfonate groups brings high water solubility and (3) B-Phen-2SO3Na is known as a selective colorimetric sensor for Fe(II) ion which operates inwide pH range (from 2 to 9).[5]

References:

[1] T. Gunnlaugsson, J.P. Leonard, Chem. Commun. 2005, 3114.[2] J. Massue, S. J. Quinn, T. Gunnlaugsson, J. Am. Chem. Soc. 2008, 130, 6900.[3] C. S. Bonnet, J. Massue, S. J. Quinn, T. Gunnlaugsson Org. Biomol. Chem. 2009, 7, 3074.[4] N. S. Murray, S. P. Jarvis, T. Gunnlaugsson, Chem. Commun. 2009, 4959.[5] H. J. Cluley, E. J. Newman, Analyst 1963, 88, 3.

P39

DYNAMIC RESOLUTION OF PHOSPHINES UNDER APPELCONDITIONS: MECHANISTIC INSIGHTS FROM USE OF A CYCLIC

PHOSPHINE AND BINOL AS ALCOHOL

Jaya S. Kudavalli, Damien J. Carr and Declan G. Gilheany*

Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, UniversityCollege Dublin, Belfield, Dublin 4, Ireland

E-mail: [email protected], [email protected], [email protected]

We recently reported the first preparatively useful dynamic resolutions of tertiary phosphines,

achieved under Appel reaction conditions by treating racemic phosphine with

hexachloroacetone in the presence of chiral cyclic secondary alcohols.[1] We now report our

first two mechanistic investigations into the origin of the stereoselectivity.

Thus 1-phenylbenzo[b]phospholane (2) as reactant was compared to its acyclic analogue

methylphenylo-tolylphosphine (1) and showed no significant difference in selectivity,

suggesting that pseudorotation of a putative pentacoordinated alkoxychlorophosphorane

intermediate is not significant.[2]

PPh

P OPh

80% ee

PPh

P OPh

78% ee

(+/-)

(+/-)

HCA, (-)-menthol

(1)

(2)

Toluene, -78 oC

HCA, (-)-menthol

Toluene, -78 oC

The asymmetric Appel reaction has been shown to proceed through formation of a pair of

unstable diastereomeric alkoxyphosphonium chloride salt intermediates.[1-2] Use of (R)-

BINOL as the alcohol source enabled isolation and characterisation (by X-ray

crystallography) of these intermediates. The variation of their diastereomeric ratio with

temperature is consistent with a mechanism operating via dynamic thermodynamic (as

opposed to kinetic) resolution.

References:

[1] E. Bergin, C. T. O'Connor, S. B. Robinson, , E. M. McGarrigle, C. P. O'Mahony, D. G. Gilheany, J.

Am. Chem. Soc. 2007, 129, 9566.

[2] J. S. Kudavalli, D. J. Carr, D. G. Gilheany, Unpublished results.

P40

Development of a Practical Synthesis of a 13C6 Labelled L-Fucoside from L-GalactoseMartina Lahmann and Mark Long

The School of Chemistry, Bangor University, Bangor, Gwynedd, LL57 2UWEmail: [email protected]

Helicobacter pylori (H. pylori) is a Gram negative bacterium which inhabits thegastrointestinal tract of 50% of the world's population. During infection, the bacteriumattaches itself to gastric epithelial cells in the gastric mucosa[1] by adhering to structures onthese cells. This is achieved through interactions between a protein on the surface of thebacterium known as the blood group antigen binding adhesin (BabA), and Lewis blood groupantigens on the cells.[2]

O

OH

OH OH

OO

NHAc

O OH

OO

OHO

OH OH

O

OOH

OHOH

O

HOOH

OH

O

OHHO

OH

O NH2

Figure 1. Lewis b hexasaccharide (1)

The Lewis b hexasaccharide (1) (Figure 1) has been synthesised earlier and used in affinitychromatography to purify the BabA protein, and to study its binding interactions. To facilitateNMR based binding studies of the hexasaccharide (1) with the BabA protein, a 13C labelneeds to be introduced.

The fucose substituent has been chosen as a suitable label as it is assumed to be involved inbinding with BabA[3] and is relatively easy to observe in NMR spectroscopy due to its methylgroup. Also, it the fucosyl residues are introduced late in the total synthesis of thehexasaccharide (1). During this project an efficient sequence of synthetic steps to produce thep-tolyl 2,3,4-tri-O-benzyl-1-thio-β-L-[UL-13C6]-fucopyranoside (3) from 13C6 labelled L-galactose (2) has been developed (Figure 2).

O

OHOH

OH13CH2

OHO

OBnOBn

OBnH313C STol

2 3, 41% yield over 8 steps

HO

Figure 2. Compound 3 has been produced in 8 steps.

1. D. Ilver, A. Arnqvist, J. Ögren, I-M. Frick, D. Kersulyte, E. T. Incecik, D. E. Berg, A. Covacci, L. Engstrand,T. Borén, Science, 1998, 279, 373-377.

2. M. Lahmann, L. Bülow, P. Teodorovic, H. Gybäck, S. Oscarson, Glycoconj. J., 2004, 21, 251–256.3. M. Aspholm-Hurtig, G. Dailide, M. Lahmann, A. Kalia, D. Ilver, N. Roche, S.Vikström, R. Sjöström, S.

Lindén, A. Bäckström, C. Lundberg, A. Arnqvist, J. Mahdavi, U. J. Nilsson, B. Velapatino, R. H. Gilman,M. Gerhard, T. Alarcon, M. López-Brea, T. Nakazawa, J. G. Fox, P. Correa, M. G. Dominguez-Bello, G. I.Perez-Perez, M. J. Blaser, S. Normark, I. Carlstedt, S. Oscarson, S. Teneberg, D. E. Berg, T. Borén,Science, 2004, 305, 519-522.

P41

DESIGN AND EVALUATION OF NOVEL ANTIPARASITIC AGENTSTARGETING PARASITE TUBULIN

Christine Mara1, Enda Dempsey2, Angus Bell2 and James Barlow1

1. Dept of Pharmaceutical & Medicinal Chemistry, School of Pharmacy,Royal College of Surgeons in Ireland, Dublin 2.

2. Dept of Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin 2


Malaria is a parasitic infection which affects approximately 300 million people worldwidecausing over one million deaths each year[1]. In order to suppress the resistance of the diseaseto drugs, antimalarials with novel mechanisms of action need to be developed. In this researchproject, plasmodial tubulin has been chosen as a potential drug target. Although tubulin ispresent in all eukaryotic cells, it may be sufficiently different from organism to organism toengage in selective targeting. Known antitubulin compounds, including current anticancerdrugs such as paclitaxel, do not have selectivity to discriminate between parasite and humantubulin.

One antitubulin compound that appears to exhibit selectivity between parasitic and humantubulin is the herbicide Trifluralin[2]. However, due to its physiochemical properties, it is apoor candidate for drug development. Amiprophosmethyl (APM) is a related compoundwhich may not have the same physiochemical limitations[3].

Analogues of APM were designed with diverse architectures around the pentavalentphosphorus atom and many of these compounds have been synthesised and characterised.These modifications include:

variations of substituents on the aromatic ring, replacement of the aromatic ring withother cycles

extension and branching of the amino chain synthesis of cyclic ox-aza analogues thiophosphoryl and phosphoryl analogues

With these modifications of the substituent groups, it is hoped that an improvement in thebiological activity of APM can be achieved.

References:

[1]. Malaria risk worldwide. Accessed 25 March 2009, from http://www.wellcome.ac.uk/.[2]. A. Bell, Parasitology Today, 1998, 14, 234.[3]. B. J. Fennell, J. A. Naughton, E. Dempsey, and A. Bell (2006) Molecular and Biochemical Parasitology,

2006,145, 226.

P42

SYNTHESIS OF NEW BIDENTATE N, O AXIALLY CHIRAL LIGANDSFOR THE ASYMMETRIC DEHYDRATIVE CYCLISATIONS OF -

HYDROXY ALLYL ALCOHOLS

Dennis Mc Cartney and Patrick J. GuiryCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



The catalytic synthesis of chiral molecules in one enantiomeric form is an important topic incontemporary organic synthesis.[1] In particular, the use of axially chiral bidentate ligandssince the success of Noyori’s BINAP ligand [2] has developed into an area of significant anddiverse interest.[3] Chiral cyclic ethers are one substrate which has been a synthetic target, dueto their prevalence in biologically active molecules.[4] Kitamura et. al. recently published abidentate N,O ligand which in combination with [CpRu(CH3CN)3]PF6 can catalyse thesynthesis of these structural units via an asymmetric dehydrative cyclisation of ɷ-hydroxyallyl alcohols to good effect (Figure 1).[5]

Figure 1 General scheme and example of asymmetric dehydrative cyclisation of ɷ-hydroxy allyl alcohols

This project focuses on the synthesis of an analogue of Kitamura’s ligand (1). The target forsynthesis (2) has a reinforced axial chirality, and a modification of the electronics of the donornitrogen through use of a quinazoline ring system. This poster will describe the retrosyntheticanalysis and progress towards the synthesis of this ligand.

Figure 2 Kitamura’s ligand 1 and analogue being synthesised 2References:

[1] Nogradi, M. Stereoselective Synthesis, VCH: Weinheim, 1995.[2] Miyashita, A.; Yasuda, H.; Takaya, H.; Toriumi, T.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc.

1980, 102, 7932[3] McCarthy, M.; Guiry, P. Tetrahedron, 2001, 57, 3809[4] Nakata, T. Chem. Rev. 2005, 105, 4314[5] Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem. Int. Ed. 2009, 48, 89

P43

9, 10-Dihydro-9, 10-ethanoantracenes:Synthesis and Anti-Proliferative Activity in Burkitt Lymphoma Cell Lines

Yvonne McNamara1, Suzanne Cloonan2, D. Clive Williams2 and Mary J. Meegan1*

1School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin,College Green, Dublin 2.

2School of Biochemistry and Immunology, Wellcome Building, Trinity Colloge Dublin,College Green, Dublin 2.


Burkitt lymphoma is a human B-cell malignancy that is known to overexpress the monoaminetransporters SERT and NET (serotonin and norepinephrine transporters respectively). Recentstudies have shown that compounds which target monoamine transporters, such as selectiveserotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA), can have a pro-apoptotic effect on lymphoma cell lines [1, 2]. Research, carried out in Trinity College’s Schoolof Biochemistry and Immunology, observed that the NET selective reuptake inhibitormaprotiline exhibits an anti-proliferative effect on the resistant BL cell line DG-75 viaautophagic cell death [3]. This effect was not observed for other NET selective compounds.The structure of maproltiline is shown below in figure 1.0. It has a characteristic tetracyclicstructure and a secondary substituted amine. Based on this evidence, a series of compoundsstructurally related to maprotiline, were designed. Modifications were made to the bridge atpositions 11 and 12 and to the side chain. These compounds were synthesised via a number ofdifferent routes using Diels-Alder and Wittig reactions. The compounds were evaluated fortheir anti-proliferative activity in various cell lines including BL cell lines MUTU-1, DG-75and a resistant leukemia cell line K562. This identified a number of compounds whichshowed an anti-proliferative effect in the low micromolar range.

Figure 1.0: Maprotiline

[1] E. J. Meredith, M. J. Holder, A. Chamba, A. Challa, A. Drake Lee, C. M. Bunce, M. T. Drayson, G.Pilkington, R. D. Blakely, M. J. S. Dyer, N. M. Barnes, J. Gordon, FASEB J. 2005, 19(7), 1187-1189.[2] A. Serafeim, M. J. Holder, G. Grafton, A. Chamba, M. T. Drayson, Q. T. Luong, C. M. Bunce, C. D.Gregory, N. M. Barnes, J. Gordon, Blood 2003, 101(8), 3212-3219.[3] S. M. Cloonan, D. C. Williams, Int J Cancer 2010.

P44

Synthesis of stable Acetyl ADPR analoguesI. Messina, a Dr. M. E. Migaud* a, and Dr. S.L.Raweb

aSchool of Chemistry, The Queen’s University of Belfast, David Keir Building, Belfast BT95AG, UK.

bSchool of Chemical and Pharmaceutical Sciences Dublin Institute of Technology, KevinStreet, Dublin D8,Ireland.

Email: [email protected]; [email protected]

Acetylated adenosine diphosphate ribose (Ac-ADPR) is formed during the deacetylation of

regulatory enzymes such as deacetylases which only function in the presence of nicotinamide

adenine dinucleotide (NAD). Ac-ADPR has also been shown to be a molecule with biological

activity of its own, activating Ca2+ gates and regulating histone-deacetylase activity through

allosteric binding. By synthesising analogues of Ac-ADPR that are chemically and

enzymatically stable, their role in the biological pathway can be established. The new entities

have to mimic the ADPR in binding the target protein but have to be slightly modified in

order to minimize the hydrolysis by the enzymes.

P45

NEW SUBSTRATES FOR RHODIUM CATALYSED ASYMMETRICHYDROBORATION USING P-N LIGANDS

Patrick J. Guiry and Ludovic MilhauCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology

University College Dublin, Belfield,Dublin 4, Ireland

e-mail: [email protected] and [email protected]

A series of substrates is being synthesised to extend the scope of Quinazolinap-Rhodiumcatalysed hydroboration reactions[1]. The regio- and diastereoselectivity withorthodivinylbenzenes is being investigated. Stilbenes with extreme electronic effects will alsogive information about achievable regio- and enantioselectivity under these conditions andallow us to compare to other ligands.[2]

The synthesis of the ligands[3] and the substrates will be described. The first results ofhydroboration will be presented.

References:

[1] P. J. Guiry, A. G. Coyne and A.-M. Carroll in Comprehensive organometallic chemistry III Vol. 10 Chap.19 (Eds.: R. H. Crabtree, D. M. P. Mingos, I. Ojima), Elsevier, UK, 2007

[2] A. Black, J. M. Brown, C. Pichon, Chem. Commun. 2005, 42, 5284[3] D. J. Connolly, P. M. Lacey, M. McCarthy, C. P. Saunders, A.-M. Carroll, R. Goddard, P. J. Guiry, J. Org.

Chem. 2004, 69, 6572

P46

DESIGN AND SYNTHESIS OF NOVEL PNA ANALOGUES

Maria Moccia and Mauro F. A. AdamoCentre for Synthesis and Chemical Biology (CSCB), Royal College of Surgeons in Ireland,

Department of Medicinal and Pharmaceutical Chemistry, 123 St Stephen’s Green, Dublin 2,Dublin.


The aim of this work is the design and synthesis of novel PNA (Peptide Nucleic Acid)analogues with improved physical and chemical properties. The analogues realized will beused to obtain the corresponding oligomers by means of the solid phase synthesis and it willbe tested for its binding properties towards natural nucleic acids (DNA and RNA). DNAstructure had undergone several chemical modifications to improve its characteristics forusing in antisense/antigene strategies;1 among these, PNA2 (Peptide Nucleic Acids) has beenone of the most successful. PNAs are homomorphous DNA analogues in which the entiresugar phosphate backbone of DNA is replaced by a neutral and achiral polyamide backboneconsisting of N-(2-aminoethyl) glycine (aeg) moieties. Each of the four nucleobases, adenine,cytosine, guanine, thymine (A, C, G, T), are attached to the backbone through a methylenecarbonyl linkers. In the past years (PNAs)3 have been extensively employed for theidentification of point mutations, isolation and blocking of genes or mRNAs. Althoughextensively used, PNAs suffer from limitations that includes (a) poor water solubility, (b) lackof cell permeability and (c) ambiguity in DNA/RNA recognition. In order to obtain PNAanalogues with improved physical and chemical properties we have designed a novel PNAmonomer (2, Fig 1). Analogue 2 has being designed as follows: (a) it contains a linear chainof six atoms, a requirement essential for the binding of resulting polymer RNAs and DNAs;(b) contains chira centresl, a property linked to preferential binding in parallel or antiparallelfashion; (c) monomers 2 could be linked in a polymer by standard peptide coupling; (d) Bases(B1-B4) are linked to the main chain by a tetrahydrofuran scaffold: this avoids formation inpolymers of multiple cis/trans rotamers as usually occurs in PNAs.

O BP

P

NH2

N O

B1

OHO

1

2

3 4

5

6

O

PO

B1HO

O-

O

O

1

2

3

4

5

6

1 2 3

Figure 2. Comparison of the structure of DNA, the new-analogue and PNA.

Figure 1References:1. Gewirtz, A. M., Sokol, D. L., Ratajczak, M. Z., Blood, 1998, 92-712; Crooke, S. T., Therapeutic

Applications of oligonucleotides, 1995, Springer-Verlag:Heidolbery.2. Nielsen, P. E., Egholm, M.; Berg, R. H.; Buchardt, O.; Science 1991, 254, 1497-1500.3. Ørum, H. Nucleic Acids Res. 1993, 21, 5332; Thiede C., Nucleic Acids Res. 1996, 24, 983; Seitz, O Angew.

Chem. 1999, 111, 2340; Angew. Chem. Int. Ed. 1999, 38, 2203; Weiler, J. Nucleic Acids Res. 1997, 25,2792.

P47

ENGINEERING A MONOOXYGENASE ENZYME FOR ENHANCEDACTIVITY TOWARDS ALKENES

Jasmina Nikodinovic-Runic1, Lucas Gursky1, Susan Molloy1, Anton Feenstra2, and KevinO’Connor*1

1UCD Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis andChemical Biology, School of Chemistry and Chemical Biology, University College Dublin,

Belfield, Dublin 4, Ireland2 IBIVU Bioinformatics, Free University Amsterdam, Amsterdam, The Netherlands


Styrene monooxygenase (SMO) is a two component flavin-dependent enzyme that produces>99% enantiopure (S)-styrene oxide (Figure 1). In Pseudomonas strains this enzyme consistsof StyA (oxygenase) and StyB (reductase) and has been used for the production of (S)-styreneoxide on a gram scale.[1] This, as well as other enantiopure epoxides are valuableintermediates in organic synthesis and recently have proved as valuable leads for thedevelopment of chiral drugs in the pharmaceutical industry.

The styAB genes from Pseudomonas putida CA-3, which encode styrene monooxygenase,were subjected to three rounds of in vitro evolution using error-prone polymerase chainreaction (PCR) with a view to improving the rate of styrene oxide and indene oxideformation. Improvements in styrene monooxygenase activity were monitored using an indoleto indigo conversion assay. Each round of random mutagenesis generated variants improvedin indigo formation with third round variants improved 9-12 fold over the wild typeenzyme.[2]

We envisage that StyAB mutants generated in this study will be a valuable addition to thechiral synthesis and technology toolbox.

N

N

N

N O

CH3

CH3

OHO2

H

H

H

NO

OO

H

H

H

O

NO

O

H

HN

OO

H

O

H

HH

OH2

H+

H+

NADPHN

N

N

N O

CH3

CH3

O

Styrene

FAD

S-StyreneOxide

Figure 1. Conversion of styrene to S-styrene oxide by SMOReferences:

[1] A. Schmid, K. Hofstetter, H. Feiten, F. Hollmann and B. Witholt, Adv. Synth. Catal., 2001, 343, 732.[2] L. J. Gursky, J. Nikodinovic-Runic, A. K. Feenstra and K. E. O'Connor, Appl. Microbiol. Biotechnol.,

2010, 85, 995.

P48

Isolation and Synthesis of Bioactive Natural Products from Marine Sources

Patrick J. Guiry and Cathal F MurphyCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



Natural products have been used for healing purposes for as long as healing has existed, it isrecorded that Hippocrates used ~400 different plant species for medicinal purposes. Evenwithin the last two centuries natural products such as Quinine, Penicillin and Paclitaxel havebeen a huge part of medicine, according to a survey by Cragg et al.1 39% of 520 new drugsapproved between 1983 and 1994 were natural products or their derivatives, of theantibacterial and anticancer drugs among these 60-80% were from natural origins. In 200060% of anticancer drugs were of natural origins and in 2001, eight of the top 30 selling drugswere from natural sources which totalled a combined US $16 billion in sales.2 Despite being arich source of biodiversity, the marine environment has not yet been fully utilised in this area,the Marine Biodiscovery Programme (MBP) aims to address this by studying marineorganisms in greater detail and as a source of biotechnological and pharmaceutical advances.

The specific focus of this project is to investigate flora and fauna of the Irish marineenvironment as a source of novel compounds with bioactivity to be used in themedical/pharmaceutical sector. Samples are received from collaboration partners at theMartin Ryan Institute (MRI) in Galway, these samples are then extracted, fractioned andsubfractioned, this is initially carried out based on solvent polarity but proceeds on to moresensitive chromatographic methods, such as column chromatography.

These extracts and fractions are then sent on to DCU to be tested for bioactivity in the areas ofpotassium (K+) channel inhibitors and T-cell modulators, which can have roles asantiarrhythmics and as anti-inflammatories respectively. Once active compounds have beenisolated within these samples they will be studied in order to determine their structure andthen a synthetic scheme will be devised for their synthesis.In parallel to this, research is being carried out on the synthesis of analogues of knownpotassium channel inhibitors. This should at the very least give some interesting StructuralActivity Relationship (SAR) data, but could also provide alternate or improved inhibitors.This research will also give a good understanding of analogue design and synthesis, whichmay then be used once the natural products have been isolated to devise and synthesiseanalogues of these compounds.

References:

[1] Cragg, G.M., Newmann, D.J., Snader, K.M., 1997 Natural products in drug discovery and development. J.Nat. Prod. 60, 52-60

[2] Sarker, S.D., Latif, Z., Gray, A.I., 2005 Natural Products Isolation 2nd Ed. 1-26

P49

SYNTHESIS OF α-S-GALACTOSYLCERAMIDESAS POTENTIAL VACCINE ADJUVANTS

N. Murphy, X. Zhu, P. Evans** Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



α-S-Galactosylceramide (1), a thioglycosidic analogue of the powerful immunostimulantKRN7000 (2),[1] recently first synthesised in our group.[2] α-Galactosylceramides activate naturalkiller T cells to produce proinflammatory T helper 1 cytokines and immunomodulatory T helper 2cytokines. Antitumor, antiviral and antibacterial effects of α-GalCer are thought to correlate withTh1 production and therefore α-GalCer analogues with Th1/Th2 biased response are of significantinterest.

S

O

HO

HO OH

HOHN

O

(CH2)24CH3

(CH2)13CH3

OH

OHO

O

HO

HO OH

HOHN

O

(CH2)24CH3

(CH2)13CH3

OH

OH

(1) (2)

Promising preliminary biological testing of α-S-GalCer and several analogues has encouraged usto broaden our range of analogues, with modification of the fatty acyl chain and development ofdisaccharide α-S-GalCer molecules. Compound (3) was recently synthesised in our lab.Introduction of aromatic groups on the fatty acyl chain of α-GalCer analogues has previouslyshown to enhance Th1 bias, possibly due to increased stability of the glycolipid/CD1d complexresulting from additional lipophilic interactions.[3] We are also investigating different substituentsat the 6-position of the sugar, starting with the introduction of galactose. Unlike the otherhydroxyl groups, the 6-position of the sugar appears to tolerate modifications without affectingthe bioactivity of the molecule.

S

O

HO

HO OH

HOHN

O

(CH2)13CH3

OH

OH

(3)

[1] M. Morita, K. Motoki, K. Akimoto, T. Natori, T. Sakai, E. Sawa, K. Yamaji, Y. Koezuka, E.Kobayashi and Hideaki Fukushima, J. Med. Chem., 38, 2176 – 2187 (1995)[2] R. T. Dere and X. Zhu, Org. Lett., 10, 4641 – 4644 (2008)[3] D. Wu, M. Fujioa and Chi-Huey Wong, Bioorg. Med. Chem., 16 1073–1083 (2008)[4] N. A. Murphy, X. Zhu and R. R. Schmidt, α-Galactosylceramides and Analogues – ImportantImmunomodulators for Use as Vaccine Adjuvants, Specialist Periodic Reports: CarbohydrateChemistry, Vol. 36.

P50

APPROACHES TO THE SYNTHESIS OF STREPTOCOCCUSPNEUMONIAE TYPE 1 CPS REPEATING UNIT

Aisling Ni Cheallaigh, Lorenzo Sernissi, Filippo Bonaccorsi, Stefan OscarsonCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

University College Dublin, Belfield, Dublin 4, Ireland.Email: [email protected]

Most bacteria are surrounded by capsule which is composed of polysaccharides (CPS). It preventscomplement opsonisation which inhibits phagocytosis by the bodies innate defence system. The CPSstructures possess a large degree of structural diversity and the different strains are characterisedaccording to variations in their CPS. The CPS structures of pathogenic bacteria are an essentialdeterminant of virulence during their invasion of the body. These structures are also antigenic so thebody’s immune system produces antibodies against them. As a result of the high specificity andantigenicity of the CPS structures they can be used as vaccines. The vaccines on the market nowadaysare conjugates of toxoided carrier proteins and the CPS which is harvested from the natural bacteria.This methodology does not provide well defined chemical structure and may have problems associatedwith the presence of biological pollutants such as pyrogens. The chemist’s solution to this is tosynthesize CPS structures. With not too complex structures this can be done at a similar cost. Thisprocess would provide well-defined structures and also avoid the risk of biological contaminants.

In the US alone Streptococcus pneumoniae causes an estimated 3,000 cases of meningitis, half amillion cases of pneumonia and 7 million cases of acute otitis media1. There are 90 different serotypesof S. pneumoniae with 30 serotypes responsible for most pneumococcal disease2. We are interested inthe production of a synthetic vaccine against Streptococcus pneumonia type 1. In this report we willgive our approach to synthesis the repeating trisaccharide unit of the Streptococcus pneumonia type 1CPS (Figure 1) as a protected thioglycosyl donor (Figure 2). This glycosyl donor can then undergosuccessive glycosylation reactions to build up oligomers of the above mentioned repeating unit.Presented here is a summary to date for the synthesis of the building blocks required for the synthesisof the protected thioglycosyl donor trisaccharide.

Figure 1. Native CPS of Streptococcus pneumonia type 13

Figure 2. Protected thioglycosyl donor trisaccharide

1 Advisory Committee on Immunisation Practice. Prevention of pneumococcal disease. Recommendations of the Advisory Committee on Immunisation Practice (ACIP).

MMWR (1997); 46(RR-8):1-24

2 Stroop, C.J.M.; Xu, Q.; Retzlaff, M.; Abeygunawardana, C.; Bush, C.A.; Carbohydrate Research 337 (2002) 335–344

3 Stroop, C.J.M.; Xu, Q.; Retzlaff, M.; Abeygunawardana, C.; Bush, C.A.; Carbohydrate Research 337 (2002) 335–344

P51

TOWARDS THE SYNTHESIS OF 1-AMINOCYCLOPROPANE-1,2-DICARBOXYLIC AICD, A POTENTIAL ANTIMALARIAL AGENT

Maeve O’Neill,1,2 Francesca Paradisi2 and Paul C. Engel1*

1 UCD Conway Institute of Biomolecular and Biomedical Research, University CollegeDublin, Belfield, Dublin 4, Ireland

2 Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,University College Dublin, Belfield, Dublin 4, Ireland


As Plasmodium falciparum, the protozian parasite responsible for 91% of the 247 millionhuman malarial infections in 2006,[1] shows an increasing resistance towards drugs, newantimalarial agents are immediately required.[2] It has been suggested that Glutamatedehydrogenase (GDH), an enzyme which catalyses the reductive amination ofα-ketoglutarate (1, Figure 1) to glutamate (2), is a potential therapeutic target.[3,4]

HO

O

NH2

OH

O

HO

O

O

OH

O

NAD(P)NAD(P)H

H2ONH41 2Figure 1: The glutamate dehydrogenase catalysed conversion of α-ketoglutarate (1) and glutamate (2).

This project focuses on the synthesis of the novel amino acid 1-aminocyclopropane-1,2-dicarboxylic acid (3, Figure 2), which will be tested as a selective inhibitor of parasite, ratherthan human, GDH. Presented here is a summary of our work to date, namely the ongoingresearch toward the development of a synthetic route by which amino acid 3 can be produced.

HO

O

NH2

OH

O

3

Figure 2: The conformationally restrained amino acid 1-aminocyclopropane-1,2-dicarboxylic acid (3)

References:

[1] World Health Organisation, in World Malaria Report 2008, 2008, p. 10.[2] N. J. White, Science, 2008, 320, 330-334.[3] World Health Organisation, in Global report on antimalarial efficacy and drug resistance: 2000-2010,

2010.[4] I. M. Aparicio, A. Marín-Menéndez, A. Bell, P. C. Engel, Mol. Biochem. Parasitol., 2010, 172, 152-

155.

P52

Enantioselective Copper Catalysis in the Intramolecular Buchner Reaction

Shane O’Neill, Sarah O’Keeffe and Anita R. Maguire*

Department of Chemistry, Analytical and Biological Chemistry Research Facility (ABCRF),

University College Cork, Cork, Ireland

As the bioactivity of enantiomers of organic compounds may differ, strategies for asymmetric

synthesis are very important, especially for pharmaceutical applications. Asymmetric catalysts provide

a particularly attractive approach as a small amount of an enantiopure catalyst can potentially provide

a large amount of an enantioenriched product. This project focuses on exploring novel copper catalysts

for application in aromatic functionalisation through intramolecular carbenoid addition, thereby

transforming the planar achiral stable aromatic ring into a chiral reactive cycloheptatriene structure

with enantiocontrol as illustrated below.1-2 While the aromatic addition reaction of diazoketones is

synthetically a very useful process, the development of an asymmetric variant has been limited. For

the majority of the asymmetric cycloadditions reported, enantioselectivities have been poor, and there

remains a lack of general applicability of chiral catalysts for aromatic addition processes.

O

N2

Me

Me O

enantiocontrol

X

X

CuClNaBARF DCM

NO

NO

Ph Ph

Preliminary results have indicated enantiopurities of 82-95% ee can be achieved across a range of

substituted diazoketones. Variation in the enantioselection of the copper catalysed intramolecular

Buchner reaction of diazoketones with the nature of the counterion has been encountered.3 An

investigation into the synthesis of novel asymmetric catalysts for application to the aromatic addition

to -diazoketones will also be discussed.

References:

1. Maguire, A.R; O’Leary, P: Harrington, F; Lawrence, S.E and Blake, A. J.Org. Chem. 2001, 66, 7166-7177

2. O’Keeffe, S.; Harrington, F.; Maguire, A.R. Synlett 2007, No. 15, 2367-2370.

3. O’Neill, S.; O’Keeffe, S.; Harrington F.; Maguire, A.R. Synlet 2009, No.14, 2312-2314.

P53

Liposomal Formulations of Photosensitizers forPhotodynamic Cancer Therapy

Edyta Paszko,1 Gisela Vaz,1 Carsten Ehrhardt,2 Mathias O. Senge,1

1Institute of Molecular Medicine, Trinity College Dublin2 School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin.

Photodynamic therapy (PDT) is a clinically approved treatment for cancer and other non-malignant diseases. This innovative method is based on the photochemical reaction betweenexogenous photosensitizing agents (PS) and tumor tissue upon a light at the appropriate wavelength.The aim of the study was to optimize photodynamic therapy using liposomal formulation of tetra-(m-hydroxyphenyl) chlorin (m-THPC, Foscan, Temoporfin) which is second-generation photosensitizercurrently available for PDT but still presents many drawback such as dark toxicity and prolonged lightsensitivity. Data show that liposomes have great potential as delivery carriers for therapeutic agents inmedicine, demonstrate higher and faster accumulation in tumor tissue and are safer compared toclassical drug formulation.

In this perspective, Foscan® has been loaded into DPPC/DPPG(dipalmitylphosphatidylcholine/dipalmitoylphosphatidylglycerol) liposomes. To these liposomespolyethylene glycol (PEG) has been attached to obtain vehicles with prolonged blood circulationlifetime, reduced uptake by organs of mononuclear phagocyte system and enhanced accumulation intumors. Recent developments in liposomal technology demonstrate that PEG-liposomes whichcirculate for a long period of time should be a better opportunity for bounding to antigen expressed ontarget tissue and thus result in better accumulation at that site.

Negatively charged liposomes encapsulated Foscan were prepared according to the Bangham method(Bangham et.al,;1965). The Temoporfin concentration was in the range between 0.5 to 2.5 mg/ml;with PEGyletated liposomes – Temoporfin concentration 1.5 mg/ml. Physicochemical properties i.eparticle size and ζ-potential were then determined using Zetasizer Nano Series (MalvernInstrument). The encapsulation efficiency was examined by measuring the fluorescence intensity ofFoscan in liposomes using microplate reader (FLUOstar OPTIMA, BMG Labtech, Offenburg,Germany) using two filters: for excitation – 410 nm and for emission - 650 nm. In order to removenon-encapsulated drug, gel filtration has been carried out, using column Sephadex cut off 6000.

Lipsomes with Foscan concentration of 0.5 to 1.5 mg/ml show the small loss of photosensitizer aftergel filtration (up to 20%); the similar results have been obtained with PEG-liposomes. All liposomesdemonstrate size about 100 nm and polydispersity index lower than 2.0 except liposomes with Foscanconcentration 2.5 mg/ml, which polydispersity index is higher than 2.0, size bigger than 100 nm andsignificantly higher loss of photosensitizer (up to 40%).

Fisrt experiments with human oesophageal cell lines shows, that liposomes encapsulated Foscan killthe cells upon illumination. Cytotoxicity of m-THPC encapsulated in liposomes was tested using MTTAssay and human cell lines and compare with control empty liposomes.

Future work involves further optimization of the assay; test a normal cell line and one derived fromBarrette's oesophagus. We are also aiming to add transferin to the terminal end of PEG-liposomes inorder to improve delivery and selectivity of the photosensitizers.

SYNTHESIS OF CONFORMATIONALLY RESTRAINED NON

Lara Pes*, Elaine O’Reilly and Francesca ParadisiUCD Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,


email:

The 7-step synthesis to a conformationally restrained amino aciddeveloped.This amino acid has great potentiality as a biologically active molecule as it shows importantsimilarities to both the neurotrasmitter GABA and glutamic acid. It has the unique feature of a1,3-disubstituted cyclobutane ring to render the compound conformationaly locked inposition, so the amino group and the carboxylic acid are located on the same side of the ring.

Fig. 1: ((1s,3s)

The coupling of the propyl ester of the amino acidbeen used to synthesise the non natural dipeptideThis opens the field of research to

Fig. 2: Non natural protected dipeptide.

References:1) . O’Reilly et al. “A novel conformationally constrained amino acid: synthesis and biological evaluation”2010, submitted to Organic and Biomolecular Chemistry

CONFORMATIONALLY RESTRAINED NON-NATURALDIPEPTIDES

, Elaine O’Reilly and Francesca ParadisiUCD Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



step synthesis to a conformationally restrained amino acid 1 (Fig. 1) has been recently

This amino acid has great potentiality as a biologically active molecule as it shows importantotrasmitter GABA and glutamic acid. It has the unique feature of a

disubstituted cyclobutane ring to render the compound conformationaly locked inso the amino group and the carboxylic acid are located on the same side of the ring.

1)-3-carboxycyclobutyl)methanaminium chloride.

The coupling of the propyl ester of the amino acid 1 and Boc protected L-phenylalanine hasbeen used to synthesise the non natural dipeptide 2 (Fig. 2).This opens the field of research to other possible novel dipeptides and short chain peptides.

2Fig. 2: Non natural protected dipeptide.

“A novel conformationally constrained amino acid: synthesis and biological evaluation”Biomolecular Chemistry

P54

NATURAL

UCD Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

(Fig. 1) has been recently

This amino acid has great potentiality as a biologically active molecule as it shows importantotrasmitter GABA and glutamic acid. It has the unique feature of a

disubstituted cyclobutane ring to render the compound conformationaly locked in cisso the amino group and the carboxylic acid are located on the same side of the ring.

phenylalanine has

other possible novel dipeptides and short chain peptides.

“A novel conformationally constrained amino acid: synthesis and biological evaluation”

P55

CLONING AND EXPRESSION OF THE CATALYTIC DOMAIN OFBACE1: A DRUG TARGET FOR THE TREATMENT OF ALZHEIMER

DISEASE

Teodolinda Petrillo and J. Paul G. Malthouse*UCD Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and

Chemical Biology, UCD SEC Strategic Research Cluster, School of Biomolecular andBiomedical Science University College Dublin, Belfield, Dublin 4, Ireland.

email: [email protected], J.Paul.G. [email protected]

Alzheimer’s disease (AD) is a neurogenerative disorder characterized by the presenceof amyloid plaques in the brain. These plaques are formed by the aggregation of beta-amyloidpeptides (AB) derived from the hydrolysis of the beta-amyloid precursor protein (APP). APPis cleaved by three proteases: the alpha-, the beta- and the gamma-secretases. The aspartylprotease, beta-secretase is especially significant because it catalyses the rate-limiting step inthe production of the beta-amyloid peptides which form the plaques which cause Alzheimer'sdisease. Therefore inhibitors of beta-secretase should be able to prevent plaque formation andso stop the development of Alzheimer's disease [1]. Knocking out beta-secretase in mice ledto a reduction in brain AB level and the mice remained healthy, fertile and normal. Thereforebeta-secretase appears to be a good therapeutic target for Alzheimer's disease.

Glyoxal peptide derivates are effective inhibitors of the aspartyl-proteases such aspepsin [2]. Therefore in this project we want to develop specific and potent glyoxal inhibitorsof BACE1. In order to optimize inhibitor design we want to use NMR to study how theseinhibitors interact with BACE1. However, for such NMR studies, a non-glycosylated, lowmolecular weight form of BACE1 is required. Therefore we are attempting to produce a lowmolecular weight form of BACE1 using just the catalytic domain (residues 43-454). Weintend to use this catalytic domain for drug development and optimization.

The catalytic domain of BACE143-454 [3] with an N-terminal His tag containing six-histidines residues was synthesized by OriGene and incorporated into pEX vector. Thisplasmid was transformed into E.coli cells for expression. Protein expression was optimized byvarying the following parameters: cell line used for expression, temperature, induction time,IPTG concentration and expression time. Currently we are optimizing the refoldingprocedure and the purification procedure.

References:

[1] Stockley, J.H.; O'Neill, C. “Understanding BACE1: essential protease for amyloid-production in Alzheimer's disease.” Cell. Mol. Life Sci. 65; 2008: 3265-3289.[2] Cosgrove, S.; Rogers, L.; Hewage, C.M.; Malthouse, J.P.G. “NMR study of the Inhibitionof Pepsin by Glyoxal Inhibitors: Mechanism of Tetrahedral Intermediate Stabilization by theApartyl Proteases.” Biochem. 46 (39); 2007: 11205-11215 .[3] Sardana, V.; Xu, B.; Zugay-Murphy, J.; Chen, Z.; Sardana, M.; Darke, P.L.; Munshi, S.;Kuo, L.C. “A General Procedure for the Purification of Human Beta-Secretase Expressed inE.Coli” Protein Expr. Purif. 34; 2004:190-196

STRATEGIES FOR THE IMMOBILIZATIONALCOHOL DEHYDROGENASE

Daniela Quaglia*UCD Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,


email:

Horse Liver Alcohol Dehydrogenase (HLADH) is an interesting enzyme as it has been usedin several chemical processes.1,2

support to allow for the recovery of the enzyme fromcould improve its stability also in the presence of organic solvents needed to maximisesubstrate solubility. Immobilization would also provide an environmentally friendly and easyway to perform enzymatic reactions eveImmobilization of enzymes has been reported in literature in the case of proteins with asimple monomeric structure (such as lipases).been so far reported.Thanks to recombinant methodologies we have been able to produce an HLADH Hison its N-terminus (figure).

This provides us both with a better and quicker way to purify the enzymeidea for its immobilization onto a special supportWe are also exploring the possibility of immobilization by more traditional strategies.goal is to create a covalent bonding between the unsupport whilst mantaining a satisfactory catalytic activ

References:

[1] D. Giacomini, P. Galletti and A. Quintavalla[2] D. Giacomini, P. Galletti, E. Emer, G. Gucciardo, A. Quintavalla, M. Pori,

2010, 8, 4117–4123[3] J. Sinisterra, J.Moreno, M.Arroyo, M.Hernáiz,[4] M. E. Riedman P. M., Heidepriem, H. H. Kohl,

His-tag

STRATEGIES FOR THE IMMOBILIZATION OF HORSE LIVERALCOHOL DEHYDROGENASE

Daniela Quaglia*, Matteo Pori, Francesca Paradisi.for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,



Horse Liver Alcohol Dehydrogenase (HLADH) is an interesting enzyme as it has been used1,2 Our research focuses on its immobilization onto a solid

support to allow for the recovery of the enzyme from the reaction mixture and we think itcould improve its stability also in the presence of organic solvents needed to maximisesubstrate solubility. Immobilization would also provide an environmentally friendly and easyway to perform enzymatic reactions even on an industrial scale.Immobilization of enzymes has been reported in literature in the case of proteins with asimple monomeric structure (such as lipases).3 HLADH is a dimer and almost no example has

ologies we have been able to produce an HLADH His

This provides us both with a better and quicker way to purify the enzyme as well as a newidea for its immobilization onto a special support (nickel beads) .We are also exploring the possibility of immobilization by more traditional strategies.goal is to create a covalent bonding between the un-tagged original protein and the solidsupport whilst mantaining a satisfactory catalytic activity. We report here our results to date.

D. Giacomini, P. Galletti and A. Quintavalla, Chem Comm, 2007, 4038-4040.D. Giacomini, P. Galletti, E. Emer, G. Gucciardo, A. Quintavalla, M. Pori,Org. and Biom. Chem

J.Moreno, M.Arroyo, M.Hernáiz, Enzyme and Microb. Techn., 1997, 21 (8), 552M. E. Riedman P. M., Heidepriem, H. H. Kohl, Applied Biochem and Biotec., 1980, 5 (1), 5

His-tag

P56

OF HORSE LIVER

for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

Horse Liver Alcohol Dehydrogenase (HLADH) is an interesting enzyme as it has been usedOur research focuses on its immobilization onto a solid

the reaction mixture and we think itcould improve its stability also in the presence of organic solvents needed to maximisesubstrate solubility. Immobilization would also provide an environmentally friendly and easy

Immobilization of enzymes has been reported in literature in the case of proteins with aHLADH is a dimer and almost no example has

ologies we have been able to produce an HLADH His-tagged

as well as a new

We are also exploring the possibility of immobilization by more traditional strategies.4 Ourtagged original protein and the solid

ity. We report here our results to date.

Org. and Biom. Chem.,

Enzyme and Microb. Techn., 1997, 21 (8), 552-558.Applied Biochem and Biotec., 1980, 5 (1), 5-9.

P57

CHARACTERISATION OF POLYACETYLENES IN CARROTEXTRACTS USING ELECTROSPRAY IONISATION QUADRUPOLETIME OF FLIGHT MASS SPECTROMETRY

Dilip K. Rai1*, Anastasios Koidis2, Ashish Rawson1, Padraig McLouglin1, and Nigel Brunton1

1Teagasc Food Research Centre Ashtown, Ashtown, Dublin, Ireland.2Institute of Agri-Food and Land Use, School of Biological Sciences, Queen’s University ofBelfast, Northern Ireland

e-mail: [email protected]

Polyacetylenes are secondary metabolites present in many plants of the Apiaceae family suchas carrots. While they are well known for their anti-fungal properties1, recent research hasrevealed that they also have anti-proliferation and anti-carcinogenic properties2. This couldlead, after confirmation, to recommendations for increased consumption of polyacetylenes inthe diet. Therefore detailed characterisation of these potentially important biomolecules isimportant and is a pre-requisite according to the current European Food Safety Authorityregulation on food with health claims3. Previous work has dealt with the characterisation ofpolyacetylenes using several techniques including mass spectroscopy (MS)4-6. However, theavailability of advanced mass spectrometry techniques such as electrospray ionisationquadrupole time-of-flight (ESI-Q-Tof) has opened up the possibility of a more completecharacterisation of these compounds which would address some of the missing informationnot provided by previous methods. In particular, negative ionisation tandem massspectrometry and accurate mass measurements used in this study provide additional structuralelucidation of the polyacetylenes. Polyacetylenes were isolated following extraction fromcarrot tissues using solid-liquid extraction with ethyl acetate; and purified using column andpreparative chromatography. An improved LC-MS method was developed where the threemajor polyacetylenes were well resolved within 35 min of the LC run compared to theprevious LC method of 110 min7. Accurate mass measurements for the major polyacetylenesfound in the carrot extracts and the fragmentation pathway of the falcarinol-typepolyacetylenes in the negative ionisation tandem mass spectrometry are presented.

References:(1) Olsson, K.; Svensson, R. Journal of Phytopathology 1996, 144, 441-447.(2) Young, J. F.; Duthie, S. J.; Milne, L.; Christensen, L. P.; Duthie, G. G.; Bestwick, C. S. J Agric

Food Chem 2007, 55, 618-23.(3) 1924/2006, A. E. N.(4) Zidorn, C.; Johrer, K.; Ganzera, M.; Schubert, B.; Sigmund, E. M.; Mader, J.; Greil, R.;

Ellmerer, E. P.; Stuppner, H. J Agric Food Chem 2005, 53, 2518-23.(5) Qian, Z. M.; Lu, J.; Gao, Q. P.; Li, S. P. J Chromatogr A 2009, 1216, 3825-30.(6) Pferschy-Wenzig, E.-M.; Getzinger, V.; Kunert, O.; Woelkart, K.; Zahrl, J.; Bauer, R. Food

Chemistry 2009, 114, 1083-1090.(7) Christensen, L. P.; Kreutzmann, S. J Sep Sci 2007, 30, 483-90.

P58

AN EASY SHORT PREPARATION OF PENTACHLOROACETONEAND TETRACHLOROACETONE BY SELECTIVE

DECHLORINATION OF HEXACHLOROACETONE UNDERAPPEL CONDITIONS

Kamalraj V. Rajendran and Declan G. Gilheany*Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

University College Dublin, Belfield, Dublin-4, Ireland

E-mail: [email protected], [email protected]

Over the last few years, pentachloroacetone (PCA) has been used as starting material in a

number of useful syntheses [1-4] involving [4+3] cycloaddition reactions. In common with

many other polychlorinated acetone derivatives, the only published preparative routes to PCA

involve the use of molecular chlorine for chlorination of acetone.[5] We report a much more

convenient laboratory preparation of both PCA and sym-tetrachloroacetone (s-TCA) by

dechlorination of hexachloroacetone (HCA) under Appel reaction conditions.[6,7] Thus

treatment of HCA with triphenylphosphine and an aromatic alcohol leads cleanly to PCA

while the use of methanol gives a high yield of s-TCA.

PPh3 / BINOLTHF

O

Cl

Cl

H

Cl

ClClrt = 5 min

PCA

O

Cl

Cl

H

Cl

ClH

PPh3 / MeOHTHF

rt = 5 mins-TCA

O

Cl

Cl

Cl

Cl

ClCl

References:

[1] K. Lee, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 5590.[2] L. C. Usher, M. Estrella-Jimenez, I. Ghiviriga. D. L. Wright, Angew. Chem. 2002, 114, 4742.[3] P. Dutar, R. A. Nicoll, Nature 1988, 332, 156.[4] R. Paitoon, H. Michael, Tetrahedron Lett. 2009, 50, 2109-2110.[5] B. Föhlisch, H. Zinser, Organic Preparation and Procedures 2004, 36, 697.[6] E. Bergin, C. T. O’Connor, S. B. Robinson, E. M. McGarrigle, C. P. O’Mahony, D. G. Gilheany, J. Am.

Chem. Soc. 2007, 129, 9566.[7] K. V. Rajendran, L. Kennedy, D. G. Gilheany, Eur. J. Org. Chem. 2010, 5642.

P59

P-STEREOGENIC PHOSPHORUS COMPOUNDS: 31P-NMR STUDIESON THE REACTIVE INTERMEDIATES IN THE ASYMMETRIC

APPEL REACTION

Kamalraj V. Rajendran and Declan G. Gilheany*Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,

University College Dublin, Belfield, Dublin-4, Ireland

E-mail: [email protected], [email protected]

We recently reported the first preparatively useful dynamic resolutions of tertiary phosphines,achieved under Appel[1] reaction conditions by treating racemic phosphine withhexachloroacetone in the presence of chiral cyclic secondary alcohols.[2] The effects of arylring substitution on the dynamic resolution of arylmethylphenylphosphines under asymmetricAppel reaction conditions were studied.[3] The dynamic resolution of tertiary phosphinesunder asymmetric Appel conditions was followed in detail by NMR spectroscopy. A transientpair of signals is always seen, identified as the diastereomeric alkoxyphosphonium salt(DAPS) intermediates. Their relative decomposition rates vary widely with alcohol/phosphinecombination and observation of the decomposition of the DAPS isomers varying with timeleads to mechanistic insight.

CCl4 or HCA

4Å MS, Toluene-78°C to r.t., ca. 12h

PhP

Ar

Me

P

dynamic resolution

up to 82% ee>95% yield

MePh Ar

OH

OMenthol

Cl

PPh ArMe

O

Cl-

DAPS

Arbuzov

Racemic

References:

[1] R. Appel, M. Halstenberg, In Organophosphorus Reagents in Organic Synthesis; J. I. G. Cadogan Ed.,Academic Press: London, 1979; Chapter 9.

[2] E. Bergin, C. T. O’Connor, S. B. Robinson, E. M. McGarrigle, C. P. O’Mahony, D. G. Gilheany, J. Am.Chem. Soc. 2007, 129, 9566.

[3] K. V. Rajendran, L. Kennedy, D. G. Gilheany, Eur. J. Org. Chem. 2010, 5642.

P60

SYNTHESIS OF UNNATURAL C-NUCLEOSIDES FOR DNA BASEDCATALYSIS

James Reck, Maria Moccia and Mauro F. A. AdamoCentre for Synthesis and Chemical Biology (CSCB), Royal College of Surgeons in Ireland,

Department of Medicinal and Pharmaceutical Chemistry, 123 St Stephen’s Green, Dublin 2,Dublin.


Our group recently reported synthetic strategies to obtain C-nucleosides of the deoxyriboseseries. We now want to extend these studies and apply the synthetic knowledge acquired tothe design and preparation of C-nucleosides that possess catalytic functions. The novel C-nucleosides proposed will be subsequently used to prepare artificial deoxyribozymes, whichwill find applications in the synthesis of important chemical intermediates. DNA catalysis oforganic reactions is a field of research still in its infancy. Because of its inherent chirality,DNA is an attractive scaffold for the design of enantioselective catalytic systems andpreviously was reported a conceptually novel DNA-based asymmetric catalyst based on aDNA double strand.1 The DNA contained an extended achiral catalytic functionality, attachedin a non-covalent manner, yet its proximity to the DNA helix allowed for direct transfer ofchirality from DNA to the catalysed reactions.2 Intrigued by these results we posed thequestion of whether an artificial DNA incorporating catalytic functionalities or made entirelyof unnatural C-nucleosides could be prepared and its synthetic efficiency demonstrated.

It has been recognised that DNA catalysis will require substantial single-stranded regions3

therefore we have focussed on the DNA hairpin motif as the scaffold to develop new DNA-based catalysts. This artificial DNA strand may be prepared by automated oligonucleotidesynthesis and an opportunely inserted organocatalyst in the sequence, as shown (fig 1.), willbe free enough in space to be catalytically active.4

T GC

A CGGT

CG

C

O

Figure 1References:1. Roelfes, G.; Feringa. B. Angew. Chem., Int. Ed., 2005, 44,

3230.2. Roelfes, G.; Boersma, A. J.; Feringa. B. Chem. Comm.,

2006, 635.3. Silverman, S. K. Chem. Comm., 2008, 3467.4. Kawakami, J.; Okabe, S.; Tanabe, Y.; Sugimoto, N.

Nuleosides, Nucleotides and Nucleic Acids, 2008, 27, 292.

P61

TANDEM ENE/IMSC FOR THE SYNTHESIS OF PYRANOSYL C-NUCLEOSIDES

Philip Redpath*

Queens University, School of Pharmacy, Medical Biology Centre, 97 Lisburn Road BelfastBT9 7BL, Northern Ireland


C- Nucleosides form a unique class of nucleosides in which the heterocycle is connectedto a sugar moiety by a C-C bond instead of the C-N bond of the natural nucleosides. As aresult, the glycosidic bond is resistant to chemical and enzymatic cleavage.1 Synthetic C-nucleosides such as benzamide ribose 1 are very potent anti-proliferative agents but alsodisplay high cytotoxic activity towards healthy cells.2 Consequently, it is essential tosynthesize novel C-nucleosides that possess structural diversity to increase specificrecognition in order to optimize enzyme and cell selectivity and maintain high levels ofinhibition.

Six-membered ring C-nucleosides have displayed promising anti-viral and anti-tumouractivities, yet very few have been prepared.3 Our group has reported initial results in theestablishment of a novel stereocontrolled route towards six-membered C-nucleosides. Thismethodology is based primarily around the tandem ene-intramolecular Sakurai cyclisation forthe construction of a range of diastereomerically pure pyranosyl C-nucleosides; morespecifically, for the synthesis of benzamide pyranosyl C-nucleosides 2.4

More recently we have demonstrated this methodologies flexibility to access differenttypes of aromatic bases for the synthesis of C-nucleosides. We have focused our work on thesynthesis of a six-membered ring tiazofurin analogue 5 and a phtalan pyranosyl C-nucleoside6 from readily accessible intermediates 3 and 4 respectively.

TBSO TBSO

R=TIPS, TBDMS

2( Z)-isomer

4

Benzamide riboside, 1

(+/-)

6

R 1 =OH , R 2 =H, R 3 =CONH 2

R 1 =H, R 2 =OH, R 3 =CONH 2

5

(+/-) (+/-)(+/-)(+/-)

References:

[1] Z. Shabarov, A. Bogdanov, Advanced Organic Chemistry of Nucleic acids. 1994, 33-70.[2] H. N. Jayaram, Curr. Med. Chem, 2002, 9, 727-792.[3] M. R. Underwood, R. G. Ferris, D. W. Selleseth, M. G. Davis, J. C. Drach, L. B. Townsend, K. K. Biron, F. L.

Boyd, Antimicro. Agents and Chemo. 2004, 48, 1647-1651.[4] P. Redpath, S Macdonald, M. E. Migaud, Org. Lett, 2008, 10, 3323-3326.

P62

TOWARDS A N. meningitidis GLYCOCONJUGATE VACCINE:SYNTHESIS OF DIFFERENTIALLY PROTECTED DISACCHARIDE

ANALOGUES OF LIPID A.

Stefan Oscarson, Heather Horan and Barbara RichichiCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,


email:[email protected], [email protected], [email protected]

Neisseria meningitidis is a gram-negative bacterium well-known for its role inmeningitis and septicemia.1 Nowadays the known commercially available glycoconjugatevaccines against N. meningitidis are based on the surface capsular polysaccharide (CPS) butonly for four of the five serotypes. Type B constitutes a problem, since the structure of theCPS mimics a human structure. All capsular serotypes contain the same LPS-structures,2

therefore an alternative approach would be to try to base a vaccine on the lipopolysaccharide(LPS) structures instead. An LPS based vaccine would be effective against all capsularserogroups, circumventing the problems of having to make a multivalent vaccine as well asthe problem connected especially with serotype B.

With native LPS structures a major complication is the toxicity of the Lipid A part due to thepresence of many fatty acid residues (amide and ester linked). In the synthetic approach thisproblem is solved by only introducing the two amide linkages. Here we report a versatilestrategy for the synthesis of disaccharides analogues of Lipid A containing two glucosamineunits where the two amine functionalities are differentially protected. Through the chosenamine groups various fatty acids are introduced to explore their role as immunogens andadjuvants. Furthermore, different attachment points of a linker for the conjugation to acarrier protein are being investigated. In particular, the location of the linker on the aminofunction should present the oligosaccharide to the immune system in a way which bettermimic the native arrangement.

References:1. Girard, M.P.; Preziosi, M.P.; Aguado, M. T.; Kienny, M.P. Vaccine, 2006, 24, 4692-47002. Plested, J.S.; Makepeace, K.; Jennings, M.P.; Gidney, M.A.J.; Lacalle S.; Brisson, J.R.; Cox, A.C.;

Martin, A.; Bird, A.G.; Tang, C.M.; Mackinnin, F.M.; Richards, J.C.; Moxon, E.R.; Infect. Immunol.1999, 67,5417.

P63

A Novel Synthesis of Rare 4-methylenecyclohex-2-enone

Keith Robertson 1, Elena Lestini1, Cormac Murphy2 and Francesca Paradisi 1

1Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,University College Dublin, Belfield, Dublin 4, Ireland

2UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield,Dublin 4, Ireland


Otteliones A and B (1, 2, Figure 1), natural products extracted from the freshwater plantOttelia alismoides1, have shown powerful anti-cancer1 and anti-tubercular2 properties. Thishas promoted interest in the synthesis of 4-methylenecyclohex-2-enone (3), a moiety of theotteliones which greatly enhances their biological activity. Indeed loss of this moiety throughtautomerisation leads to a reduction of biological activity of up to 80%2,3.

OOCH3

OH

OOCH3

OH

O

1 2 3

Figure 1: Ottelione A (1), Ottelione B (2) and 4-methylenecyclohex-2-enone (3).

Few syntheses of the molecule are currently available4,5 and these can involve harshconditions. Presented here is a novel synthesis of 4-methylenecyclohex-2-enone from a Diel-Alder methanesulphonate adduct in up to 70% yield, under mild conditions. The syntheticpathway consists of four steps from commercially available starting materials and isenvisaged to give access to a range of 4-methylencyclohex-2-enone derivatives, with potentialbiological activity.

References

1. Ayyad, S.; Judd, A.; Shier, W.; Hoye, T. Journal of Organic Chemistry 1998, 63, 8102-8106.2. Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.; Prod'homme, F.; Herman, F.; Lavelle, F.; Leboul,

J.; Vuilhorgne, M. Mol Pharmacol 2000, 57, 553-63.3. Leboul, J.; Provost, J.; French patent WO96/00205, 1996. Chem. Abstr. 1996, 124, 2422964. Birch, A.; J. Proc. R. Soc. N. S. W. 1949, 83, 2455. Jung M.; Rayle, H.; Synth. Commun., 1994, 24, 197-203

P64

SYNTHESIS OF PORPHYRIN OLIGOMERS FOR APPLICATIONS INPHOTODYNAMIC THERAPY

Aoife Ryan and Mathias O. Senge*

Centre for Chemical Synthesis and Chemical Biology, School of Chemistry,Trinity College Dublin, Dublin 2, Ireland. e-mail: [email protected], [email protected]

Photodynamic therapy (PDT) is a branch of cancer treatment which utilises the combinationof a drug and light to induce a cytotoxic effect in cancerous or other unwanted tissue. Arequirement this application is a capacity to absorb energy in a region of the electromagneticspectrum that is as far red shifted as possible to enable deeper penetration of the exciting lightinto the tumour and an emission that is of the appropriate energy to convert singlet oxygen tothe toxic triplet oxygen. Also, this application desires a level of targeting to, and accumulationin, the tissue that is to be treated. Modifications to the porphyrin structure to accommodatethese conditions1 can be achieved by extending the conjugation of the porphyrin π-system,which will cause a bathochromic shift in the absorption spectrum. In our work, a series ofsymmetric and unsymmetric dimeric and trimeric porphyrin systems which are connected viaconjugated linkers were synthesized. The unsymmetric dimers contain both hydrophilic and

hydrophobic entities, which could enhance the amphipilicity of the compound and henceassist accumulation in the target tissues. The symmetric oligomers primarily incorporate thephenylacetylene linker and also some oligomers have free meso positions, enabling furtherchemistry to be carried out to enhance their PDT effect.2 Porphyrins with modified carbazolesubstituents, shown above, have found interest in organic light emitting diode (OLED)studies.3 We have developed a novel synthetic scheme for carbazole linked porphyrin dimersand are now using similar principles to construct derivatives applicable for PDT.

1Sternberg, E. D.; Dolphin, D.; Bruckner, C. Tetrahedron, 1998, 54, 4151-4202

2 Feng, S.; Senge, M.O. J. Chem. Soc., Perkin Trans. 2001, 1, 1030-10383 Wiehe, A.; Shaker, Y. M.; Brandt, J. C.; Mebs, S.; Senge, M. O. Tetrahedron, 2005, 61, 5535-5564.

N

NH N

HN

LINKER

A

BN

HNN

NH

C

C

D

A

Linker =

N

P65

APPLICABILITY OF BETA-DIKETIMINATE RUTHENIUM(II)-

ARENE COMPLEXES IN HOMOGENEOUS LEWIS ACID CATALYSIS

OF DIELS-ALDER REACTIONS

Dominique F. Schreiber and Andrew D. Phillips

Centre for Synthesis and Chemical Biology (CSCB), School of Chemistry and ChemicalBiology, University College Dublin, Belfield, Dublin 4, Ireland.


There is increasing literature describing the use of -diketiminate ligands in homogeneoustransition-metal catalysis.1) The -diketiminate ligand composed of a chelating diazo scaffoldfeatures all the necessary characteristics of a modern, versatile ligand for selectivehomogeneous catalysis. Most importantly, the presence of the flanking aryl moieties induces ageometrically well defined enzyme-type substrate pocket around the metal. Furthermore, thecoordination of the ligand to the metal results in a strong metal to ligand charge transfer andallows tuning of the Lewis acidic strength of the active metal center.

Currently the majority of modern pharmaceuticals being commerically sold feature at leastone cyclic ring structure. The Diels-Alder reaction is a highly atom efficient synthetic methodto fuse three unsaturated bonds together to form a six-memebered ring. Selectivity andactivation of substrates is the central focus of modern homogeneous catalysis. The latterissues are successfully addressed with ruthenium(II)-arene complexes.2) In the present work,the synthesis and characterisation of novel ruthenium(II) complexes featuring electron-withdrawing -diketiminates and the application towards Lewis acid catalysis of thecycloaddition between ,-unsaturated aldehydes and diene substrates such ascyclopentadiene is investigated (as shown below).

[1] Phillips et al., Organometallics, 2007, 26, 1120-1122.[2] Odenkirk et al., J. Am. Chem. Soc. 1992, 114, 6392-6398. Kündig et al., Angew. Chem. Int. Ed. 2001,

40(23), 4481-4485. Carmona et al., Dalton Transactions 2008, 3328-3338.

P66

SMALL MOLECULES FOR FLUORESCENCE IMAGING ANDCANCER DIAGNOSTICS

Natalia N. Sergeeva, Marion Donnier-Marechel, Gisela Vaz, Anthon M. Davies and MathiasO. Senge

Medicinal Chemistry, Institute of Molecular Medicine and SFI Tetrapyrrole Laboratory,School of Chemistry, Trinity College Dublin, Ireland


Oesophageal cancer is one of the common and aggressive and it has shown a dramaticincrease in Europe and North America in a past few years. Due to a late detection mechanism,the survival rates are about 10 %.[1-3] Therefore, an early diagnosis is essential to increase achance of successful treatment and cancer spread prevention. Molecular imaging is one of themost powerful tools in modern science. In past few decades, this technology became centralin biology, particularly, in bioassays and cell imaging, cancer research and clinical trials inmedicine.

We have developed the series of the fluorescent compounds that can be used for cell imagingand cancer diagnostics. The 12 compounds have been prepared in up to 90%. They can beused as fluorescence markers for endoplasmic reticulum in both live- and fixed cells. Currentstudies show that the material can be used in distinguishing between normal and cancer celllines.The studies on localisation, incubation times and concentration ranges for the wholeseries were carried out on two cell lines OE21 and HET-1A. It was found that thefluorescence images can be already obtained after 20 min of incubation at concentrations of 1-27µM. In vitro studies on the both cell lines have shown that these compounds are localisingin endoplasmic reticulum. The experiments were carried out on live- and fixed cells and showthe same localisation of the dyes in both cell lines.

References:

[1] S. Villette, S. Pigaglio-Deshayes, C. Vever-Bizet, P. Validire and G. Bourg-Heckly,Photochem. Photobiol. Sci., 2006, 5, 483.

[2] C. P.Wild and L. J.Hardie, Nat. Rev. Cancer, 2003, 3, 676.[3] D. M. Parkin, F. Bray, J. Ferlay and P. Pisani, CA Cancer J. Clin., 2005, 55, 74.

P67

A Novel Organic Fluorophore and its Potential Application as a BiologicalProbe

Dean St. Mart*1, Denisio Togashi2, Alan G. Ryder2, and John Stephens1.1 Organic Synthesis Research Lab, Department of Chemistry, National University of Ireland

Maynooth, Maynooth, Co. Kildare, Ireland.2 Nanoscale Biophotonics Laboratory, School of Chemistry, National University of Ireland,

Galway, Galway, Ireland.

*email: [email protected], [email protected]

The extrinsic labelling of biomolecules for identification and/or quantification is one of themost common methodologies in the lifesciences. This labelling, for example, can be carriedout with (i) radioactive materials or (ii) compounds with absorption and/or fluorescenceproperties.[1] With the advent of confocal microscopy and live cell imaging, fluorescenceoffers the tools to visualise and quantify the chemical and biochemical processes in livingcells. We are particularly interested in a new class of organic fluorophores which have thepotential to be synthetically modified to form covalent or noncovalent linkages with a giventarget of interest (e.g. protein).We are developing a versatile heterocyclic (1,2,3-triazine) fluorophore (1) that can be used inbiomolecular applications.[2] This work builds on preliminary photophysical studies whichreported 1,2,3-triazines with a dual UV absorption at ca. 310 and 390 nm, and fluorescentemission at ca. 480 and 528 nm. The significant Stokes shift offers the potential forbiological fluorescent labelling experiments (Figure 1.). Consequently, analogues have beendesigned which show further promise as biological labels and/or sensors. Herein is asummary of our work to date, including synthetic routes based upon an interesting Huisgen1,3-dipolar cycloaddition that undergoes a ring expansion to generate the 1,2,3-triazinefluorophore, and a brief outline of our fluorescent spectroscopy results thus far.

Figure 2. Absorption and emission spectra for compound 1, with structure of 1 inset [2]

References:[1] M. Sameiro T. Gonçalves, Chem. Rev. 2009, 109, 190–212[2] R. N. Butler, A. M. Fahy, A. Fox, J. C. Stephens, P. McArdle, D. Cunningham, A. G. Ryder, J. Org.

Chem., 2006, 71, 4596

P68

SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF A SERIES OFCARBOHYDRATE FATTY ACID GLYCOCONJUGATES

Mark Tallona, Julie Dunneb, Paula Bourkeb, Sarah L. Rawec

aFocas Institute, Dublin Institute of Technology, Camden Row, Dublin 8, Ireland. bSchool ofFood Science and Enviromental Health, Dublin Institute of Technology, Cathal Brugha

Street, Dublin 1 and cSchool of Chemical and Pharmaceutical Sciene, Dublin Institute ofTechnology, Kevin Street, Dublin 2


The aim of this work is the synthesis and biological evaluation of a series of glycolipids in

which a monosaccharide is linked at the anomeric position to a fatty acid-like alkyl chain via

a 1,2,3-triazole linkage1,2. Fatty acids such as lauric acid and fatty acid derivatives including

monolaurin have demonstrable antibacterial activity and the goal of this work is to enhance

this activity by conjugation to a sugar. In the current work, we hope to extend the studies

previously reported by Dunne et al1. by preparing a new library of glycolipids which can be

prepared simply from commercially available and affordable starting materials4. We have

assessed the biological activity of these compounds against a range of microorganisms

including those of particular interest to the food industry.The synthetic route to our library of

compounds was chosen to exploit the copper (I) catalysed Huisgen’s reaction developed by

Sharpless and Meldal4,5. This allowed us to synthesize a small library of compounds relatively

in a short time which were found to have only weak to moderate activity against

Staphylococcus aureus. Further evaluation is underway against other organisms: Listeria

Monocytogenes and Escherichia Coli.

References:

1. Nobmann, P., et al., The antimicrobial efficacy and structure activity relationship ofnovel carbohydrate fatty acid derivatives against Listeria spp. and food spoilagemicroorganisms. International Journal of Food Microbiology, 2009. 128(3): p. 440-445.

2. Bock, V.D., et al., 1,2,3-Triazoles as peptide bond isosteres: synthesis and biologicalevaluation of cyclotetrapeptide mimics. Organic & Biomolecular Chemistry, 2007.5(6): p. 971-975.

3. Kabara, J.J., et al., Fatty-acids and derivatives as antimicrobial agents. AntimicrobialAgents and Chemotherapy, 1972. 2(1): p. 23-&.

4. 38. Meldal, M. and C.W. Tornoe, Cu-catalyzed azide-alkyne cycloaddition.Chemical Reviews, 2008. 108(8): p. 2952-3015.

5. Kolb, H.C. and K.B. Sharpless, The growing impact of click chemistry on drugdiscovery. Drug Discovery Today, 2003. 8(24): p. 1128-1137.

P69

SYNTHESIS OF CAPSULAR POLYSACCHARIDE STRUCTURES OFCRYPTOCOCCUS NEOFORMANS

Rebecca Ulc, Stefan Oscarson*



Cryptococcus neoformans is an opportunistic fungal pathogen that causes severe diseasesprimarily in immunocompromised individuals (e.g. HIV positive patients).[1] C. neoformans issurrounded by a thick layer of capsular polysaccharides (CPS), which is an importantvirulence factor. In order to investigate the immunobiological properties of the fungal CPS,and thereby aid glycoconjugate vaccine development, we are synthesising part structures ofthe fungal CPS.

Currently, we are focusing on the synthesis of a hexasaccharide building block (1)corresponding to the serotype A structure of C. neoformans. This sugar contains -Manp, -Xylp, -GlcpA and 6-O-acetyl motifs. It is our idea to use this oligosaccharide as buildingblock in the construction of larger polysaccharide structures (dodecasaccharides) by using ablock approach.

O

O O

O

BnOAcO

BnO

O

OBnOBnO

BnO

O

OBnOBnO

BnO

BnO

O

SEt

AcO

O

OBnOBnO

BnO

BnO

NAPO

OBnO

Hexasaccharide corresponding to serotype A

1

The hexasaccharide may be obtained by a [2+4] glycosylation of a -linked GlcpA-Manpdisaccharide with a (Xylp-Manp)2 tetrasaccharide. A reliable methodology to access relatedthioglycoside building blocks has been developed previously in our group.[2,3,4] We present animproved synthetic pathway to the glucuronic acid-containing disaccharide. Synthetic aspectswill be discussed, such as the formation of a -glycosidic linkage using thetrichloroacetimidate method, the regioselective introduction of 6-O-acetyl groups and theoxidation of the primary position of the glucose moiety to the glucuronic acid motif followedby benzylation to give the benzyl ester protected GlcpA-Manp disaccharide donor.

References:

[1] E. Brummer, Mycopathologia 1999, 143, 121-125.[2] M. Alpe, P. Svahnberg, S. Oscarson, J. Carbohydr. Chem. 2003, 22, 565-577.[3] M. Alpe, P. Svahnberg, S. Oscarson, J. Carbohydr. Chem. 2004, 23, 403-416.[4] J. Vésely, L. Rydner, S. Oscarson, Carbohydr. Res. 2008, 343, 2200-2208.

P70

The Synthesis and Investigation of β-Lactam Ring as Scaffold for Novel BioactiveCompounds

Shu Wang*, Mary.J.Meegan

School of Pharmacy & Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology,Panoz institute, Trinity College Dublin, Dublin 2, Ireland

E-mail address: [email protected]

The β-lactam (azetidin-2-one) ring structure has been identified as a suitable scaffold formany bioactive products with antiviral, antibiotic, antifungal, antiproliferative properties. Useof the β-lactam ring may provide access to analogues of these products with increasedpotency, improved stability, and increased solubility. The improved characteristics are shownto be useful for further drug development. Derivatives of azetidinone with diverse andinteresting activities occupy a central place among medicinally important compounds.Although the various naturally or synthetic β-lactam are best known for their potentantibacterial activities, examples of azetidin-2-one have recently been investigated asinhibitors of proteases such as leukocyte elastase and gelatinase. [1]

In the present work, the use of the four-membered azetidin-2-one (β-lactam) ring asscaffold for bioactive compounds such as combretastatin A-4 (CA-4) [2] analogues isinvestigated in an effort to gain access to novel agents that possess the potent anticanceractivity associated with CA4 which has been shown to be a cancer cell growth inhibitor, witha mechanism of action of tubulin dynamics disruptor and binding at the colchicine site. [3] Theβ-lactam ring can be formed by the Staudinger reaction [4] between an imine and a ketene. Theimine was synthesized via the condensation of the appropriately substituted benzaldehyde andaniline. The compounds which were synthesized have been analysed by 1H-NMR & 13C-NMR, IR spectroscopy and high resolution mass spectroscopy. A library of 1,4-diarylazetidin-2-one with vinyl type substituent at C-3 has been synthesised. The stereochemical outcome ofthe Staudinger reaction has been determined to give predominantly cis products by analysis ofthe H-3/H-4 coupling constant J values. The mechanism of antiproliferative activity exhibitedby these products is characterised through extensive in vitro investigation in MCF-7 breastcancer cell line. Preliminary molecular modeling studies will be presented.

Reference:[1] Fides Benfatti, Giuliana Cardillo, Luca Gentilucci, and Alessandra Tolomelli, "Synthesis of Four-Membered Ring Spiro-β-lactams by

epoxide Ring-Opening", Eur. J. Org. Chem. 2007, 3199-3205[2] Pettit, G. R. Sheo Bux Singh Boyd, M. R. Hamel, E. (1995), "Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatins A-

4, A-5, and A-6", Journal of Medicinal Chemistry 38: 1666–1672[3] Lin CM, Ho HH, Pettit GR, Hamel E. Antimitotic natural productscombretastatin-A-4 and combretastatin-A-2: studies on the mechanism

of their inhibition of the binding of colchicines to tubulin", Biochemistry 1989; 28: 6984-91[4] Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51

RCSI Labs TCD Labs UCD Labs

Centre for Synthesis and Chemical Biology,University College Dublin, Belfield, Dublin 4, Ireland

Tel: +353-1-716 2302 Fax: +353-1-716 2501 Email: [email protected]: www.ucd.ie/cscb


Funding for the establishment of the Centre for Synthesis and Chemical Biology (CSCB) wasapproved by the Higher Education Authority’s Programme for Research in Third Level

Institutions in December 2001. The CSCB assembles researchers in the chemical sciencesfrom University College Dublin (UCD), Trinity College Dublin (TCD) and the Royal College of

Surgeons in Ireland (RCSI).

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