symposium on translating chemistry into medicines · symposium on translating chemistry into...

NORM'14 trans-‐Chem2Med

1

Symposium on Translating Chemistry into Medicines

Whether the source is nature or the lab, medicines are chemicals. Complex, perhaps, with fascinating molecular architecture, yet new chemistry continues to be the driving force in the quest for the discovery and production of new medicines. "Translating chemistry into medicines" is the endeavor that motivates the chemists who will

talk at our symposium. NORM'14, Tuesday, June 24, University Center Theater, University of Montana campus.

Organizer: N.R. Natale http://biomed.health.umt.edu/users/nicholasnatale 9:00-9:40 Andrea Stierle, D.B. Stierle, T. Girtsman, C. Antczak, H. Djaballah, University of Montana "Bioprospecting in the Berkeley Pit: Extremophilic Microbes in Drug Discovery" http://biomed.health.umt.edu/users/andreastierle

9:40-10:20 Mike Mosher, Northern Colorado University "Acridines with Potential Pharmaceutical Significance" http://www.unco.edu/nhs/chemistry/faculty/mosher/index.html Coffee Break 10:20-10:40 10:40- 11:20 Matt Peterson, Brigham Young University , "Synthesis and Evaluation of a Novel Inhibitor of Orotidylic Acid Decarboxylase. A Useful Construct for the Development of Anticancer Nucleosides." http://www.chem.byu.edu/faculty/matt-a-peterson/ 11:30-1:30 Lunch 1:30-2:10 Cynthia A. Maryanoff, Baruch S. Blumberg Institute (Doylestown) as Professor (with Distinction) of Experimental Therapeutics and Medicinal Chemistry and the Pennsylvania Drug Discovery Institute (Doylestown, PA) as Professor of Drug Delivery, "Dynamics of Drug Release from two different polymer systems in drug-eluting cardiovascular stents" 2:10-2:50 Bruce E. Maryanoff, L.J. Leman, Y.Zhau, T. Imura, L.K. Curtuss, M.R. Ghadiri, Department of Chemistry, The Scripps Research Institute, "Novel mimetics of apolipoprotein A-I as anti-atherosclerosis agents" Intermission 2:50 -3:10 3:10-‐3:50 Todd Talley, Idaho State University "Searching for specificity: The acetylcholine binding protein as a tool for drug discovery" 3:50-‐4:30 Cliff Berkman, Washington State University "Enzyme Inhibitors as Platforms for Prostate Cancer Diagnostic & Therapeutic Agents" http://organic.chem.wsu.edu/cliff-berkman/ 4:30 -‐ 5:10 Charles M. Thomson, University of Montana “Chemical Repurposing – Beneficial Neuroimaging Probes Derived from Toxic Organophosphates.” http://biomed.health.umt.edu/users/charlesthompson Sponsored by the ACS Division of Medicinal Chemistry (MEDI), the University of Montana College of Health Professions and Biomedical Sciences (CHPBS), and the Department of Biomedical and Pharmaceutical Sciences (BMED), Med Chem 101, and the Western Montana Clinic. For more Sponsor info, see pages 17-18. Speaker Information:


2

Dr. Cynthia A. Maryanoff

Baruch S. Blumberg Institute (Doylestown) as Professor (with Distinction) of Experimental Therapeutics and Medicinal Chemistry and the Pennsylvania Drug Discovery Institute (Doylestown, PA) as Professor of Drug Delivery

“Dynamics of Drug Release from two different polymer systems in drug-eluting cardiovascular stents” Abstract: When molecules that are potent and effective compounds are found to have poor oral bioavailability, device delivery may be an effective avenue for their use. One such molecule is rapamycin. This presentation focuses on the dynamics of rapamycin [aka sirolimus] release from two different polymer systems using drug-eluting cardiovascular stents as the exemplar delivery device. Brief Biosketch: Dr. Cynthia A. Maryanoff received her B.S. in chemistry from Drexel University in 1972 and completed her Ph.D. and postdoctoral work at Princeton University. She joined Medicinal Chemistry at Smith, Kline & French. In 1981, she moved to Johnson & Johnson (J&J), and advanced to the highest scientific position in the company, Distinguished Research Fellow, and retired in 2013, after 32 years. She is now affiliated with the Baruch S. Blumberg Institute (Doylestown) as Professor (with Distinction) of Experimental Therapeutics and Medicinal Chemistry and the Pennsylvania Drug Discovery Institute (Doylestown, PA) as Professor of Drug Delivery. Scientific Contributions. Dr. Maryanoff has made numerous contributions in process organic chemistry, as well as product development. She is an internationally recognized expert in drug development. Her innovations in process development contributed to the commercial success of pharmaceutical products such as TOPAMAX, for epilepsy and migraine, REMINYL for Alzheimer’s disease, and ACEON and VASCOR for cardiovascular disorders; the first multi-ton scale-up of PERAMIVIR, an anti-influenza neuraminidase inhibitor; SURFAXIN (KL4), a 21-mer peptide pulmonary surfactant for respiratory distress syndrome, CLADRABINE for MS, and ULTRAM® for pain. Drug Evaluation Chem Pharm focused on rapid turn-around for development compounds allowing compounds to “fail early” by rapidly identifying the failure points of compounds and quickly moving to the next candidate. Successes from this approach led to EDURANT for AIDS and SIRTURO for tuberculosis and INVOKANA.™ for type 2 diabetes. Dr. Maryanoff also made significant contributions to devices such as the drug-eluting stents CYPHER and NEVO. She has an outstanding record of publications and patents including >100 scientific papers, >200 published abstracts, 3 books, 67 U.S./European patents (issued or pending). Under her capable leadership, resources were coordinated and focused to achieve simultaneously scientific innovation and corporate goals. Service. Dr. Maryanoff has been very active in the American Chemical Society, serving on the Executive Committee of the ACS Organic Chemistry Division for 25 years, holding positions by national election, including Chair in 1997 and ACS Councilor currently. Member, Executive Committee, ACS, Division of Organic Chemistry (1988-2015); Chair, 1997, Executive Committee, Councilor or Alt. Councilor (1992-2003; 2010-2012; 2013-2015); chair of Travel Awards (1989-current); Member, ACS Development Advisory Board (2011 – 2014); Member, ACS Task Force on Vision 2025, 2012-3 Assoc. Member, American Chemical Society, Committee on International Activities, 2013, 2014; Member, ACS Task Force on Multidisciplinarity of Chemistry, 2004-5, Member, Advisory Board of Journal of Organic Chemistry, 2000-2004; Member, ACS Medicinal Chemistry Long Range Planning Committee (1999-2003); Member and Chair, Search Committee for Editor of Accounts of Chemical Research, 1995; Member, Search Committee for Editor of Journal of Organic Chemistry, 1999;


3

Member, Committee on Science, ACS (1992-1995); Member, ACS Books Advisory Board (1994-1997); Member, Advisory Board of Chemical & Engineering News (1990-1992); Member, A. C. Cope Scholar Award Canvassing Committee (1990-1993; chair 1993); Member, Advisory Board of the ACS Petroleum Research Fund (1986-1989); Organizer and chair of 23 Award Symposia at ACS national meetings; Chair of 13 general sessions at ACS National Meetings In addition to ACS service, she serves/d as a Member, Advisory Council of the College of Arts and Sciences at Drexel University (1998-present); Board Member, Forget Me Not Foundation (2010-current); Member, Drexel University Dean Review Committee (2012-2013); Member, Advisory Council of the Gordon Research Conferences (2000-2003); Member, AAAS Nominating Committee (1996-2000); chair 1998-99; Member, NSF Fellowship Review Panel, 1993; Member, Medicinal Chemistry Study Section, NIH Division of Grants (1988-1992); Member, N. I. H. Med. Chem. Small Business Innovation Research Program Review, 1993; Member, Editorial Advisory Board for Heteroatom Chemistry (1988-1999); Member, NCI Committee for Proposals to Synthesize Pharmaceutical Agents; Editor (with B. E. Maryanoff) of the series "Advances in Medicinal Chemistry" (JAI Press, Inc), 1988-1999. Awards & Honors. Dr. Maryanoff received the national award of the American Chemical Society (ACS) Garvin-Olin Medal in 1998 for her scientific accomplishments in process chemistry. Her adept management and innovative ideas were recognized on a national level by the ACS with the Earle B. Barnes Award for Leadership in Chemical Research Management (2005) and the Henry F. Whalen, Jr. Award for Business Development from ACS Division of Business Development and Management (2007). She received the ACS Philadelphia Section Award (1991); a TWIN Award (Tribute to Women and Industry, 1997); a Drexel University Distinguished Alumni Achievement Award (1999); the Philadelphia Organic Chemist Club Award (1999); and a U of Pennsylvania Trustee’s Council: Women in Chemistry Award (2001); the American Women in Science Elizabeth Bingham Award (2010). Dr. Maryanoff was recognized internally by several awards including J&J’s Philip B. Hofmann Research Award. She was elected Fellow of the American Association for the Advancement of Science (AAAS) in 1992 and the ACS in 2009 (inaugural year). Representative Cynthia Maryanoff Publications: The reaction of amines with methylene chloride. Evidence for rapid aminal formation from N-methylenepyrrolidinium chloride and pyrrolidine. Mills, J. E.; Maryanoff, C. A.; McComsey, D. F.; Stanzione, R. C.; Scott, L. J. Org. Chem. 1987, 52, 1857. Mechanistic aspects of the ligand-assisted nucleophilic addition reaction. Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc. 1990, 112, 9393. Asymmetric induction in an enammonium-iminium rearrangement. Mechanistic insight via NMR, deuterium labeling, and reaction rate studies. Application to the stereoselective synthesis of pyrroloisoquinoline antidepressants. Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Graden, D. W.; Maryanoff, B. E. J. Am. Chem. Soc. 1990, 112, 3567. Chemical process synthesis of β-amino acids and esters. Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A.

Curr. Med. Chem. 1999, 6, 955. Cyclizations of N-acyliminium ions. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.

A. Chem. Rev. 2004, 104, 1431.


4

Bruce E. Maryanoff Scripps Research Institute

"Novel mimetics of apolipoprotein A-I as anti-atherosclerosis agents" Abstract Body: Cardiovascular disease is the major cause of death in developed countries despite the widespread use of lipid-lowering drugs. Consequently, a high level of interest exists in identifying new modes of therapy for atherosclerosis, such as modulating high-density lipoprotein (HDL), which protects against atherosclerosis. Because apolipoprotein A-I (apoA-I), the key protein component of HDL, has anti-atherosclerotic properties, numerous efforts have been devoted to mimicking apoA-I with linear, a-helical, amphiphilic peptides. We have been investigating the design, synthesis, and efficacy (in vitro and in vivo) of branched, multivalent apoA-I mimetic molecules with 2–4 copies of an amphiphilic peptide attached to a core scaffold. Multivalent apoA-I mimetics based on 23-mers were better than monomer in effluxing cholesterol from mouse macrophages and in remodeling mature plasma HDL particles into nascent lipid-poor HDLs. These peptide constructs were remarkably stable toward enzymatic digestion in vitro, and displayed long half-lives and desirable pharmacokinetics in mice. Constructs comprised of multiple 16-mers were also explored. The multivalent apoA-I mimetics were combined with phospholipids to produce discoidal HDL-like nanoparticles, which functioned in vivo in mice to remodel large native HDLs into small, lipid-poor HDLs. Robust atheroprotective activity was observed in 10-week studies with LDL receptor-null mice fed a high-fat diet. Brief Biography for Bruce E. Maryanoff, Ph.D. Dr. Bruce E. Maryanoff was born on 26 February 1947 in Philadelphia, Pennsylvania, USA. He earned a B.S. degree in chemistry (1969) and a Ph.D. degree in organic chemistry (1972) from Drexel University. After postdoctoral studies at Princeton University, he joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974. He advanced on the scientific ladder in various Johnson & Johnson pharmaceutical units to the highest scientific position in the company, Distinguished Research Fellow. He retired from Johnson & Johnson in 2010, after 36 years, and is now affiliated with The Scripps Research Institute (La Jolla, CA), the Pennsylvania Drug Discovery Institute (Doylestown, PA), and the Baruch S. Blumberg Institute (Doylestown), Scientific Contributions. Dr. Maryanoff has made numerous contributions in medicinal and organic chemistry. He is an internationally recognized expert in drug design and discovery. From 1976−1992, he worked on central nervous system therapeutics, focusing on anticonvulsants and antidepressants. Dr. Maryanoff discovered and championed TOPAMAX® topiramate, a unique sugar sulfamate derivative, which is sold worldwide for treating epilepsy and migraine headache (achieved peak sales of >$2 billion/year). Topiramate is a main component of the antiobesity drug Qsymia (VIVUS, Inc.). From 1991-2010, he pursued therapeutics for cardiovascular disease, metabolic disorders, pulmonary inflammation, and epilepsy. Since 1990, his drug research has dealt with structure-based drug design; peptides and peptidomimetics; inhibitors of diverse enzymes, especially serine proteases (thrombin, factor Xa, tryptase, cathepsin G, chymase) and kinases (protein kinase C-β, glycogen synthase kinase-3β, ketohexokinase); integrin (GPIIb/IIIa, αvβ3/5, α4β1/7) antagonists; and ligands for G-protein-coupled receptors (protease-activated, urotensin-II, vasopressin, ADP P2Y12). His efforts led to 23 compounds entering preclinical development, 13 of which advanced into human clinical trials, with three compounds reaching late-stage clinical development. In organic chemistry, he made seminal contributions to the stereochemistry and


5

mechanism of the Wittig olefination reaction; adapted cobalt-mediated [2+2+2] alkyne cyclotrimerizations to macrocycle synthesis; and devised novel, self-assembling collagen-mimetic peptides. His chemistry work also dealt with heterocycle synthesis, N-acyliminium cyclizations, hydride reductions, carbohydrates, and nucleosides. His current research involves epigenetic processes, especially histone-modifying enzymes, and lipid nanoparticles containing apoA-1 mimetics. Dr. Maryanoff has published 275 scientific papers, is an inventor on 96 U.S. Patents, has presented 185 invited lectures, and has mentored 11 postdoctoral associates. Awards & Honors. Dr. Maryanoff has received three American Chemical Society (ACS) national awards, the Heroes of Chemistry Award-2000, Award in Industrial Chemistry-2003, and E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances-2013; also the 2009 Edward E. Smissman Award from the ACS Division of Medicinal Chemistry. He was inducted into the ACS Medicinal Chemistry Hall of Fame in 2008. He received a Philadelphia ACS Section Award (1984), a Philadelphia Organic Chemists' Club Award (1995), and the Prix Paul Ehrlich (2010). He was honored with a Johnson Medal for R&D for discovery and development of TOPAMAX®, and was twice a recipient of Johnson & Johnson's Philip B. Hofmann Research Scientist Award. He was recognized by Drexel University as a notable alumnus with several awards, including election to the Drexel Alumni 100 Club. Dr. Maryanoff was elected Fellow of the American Association for the Advancement of Science (AAAS; 1989), the Royal Society of Chemistry (2000), and the ACS (2009; inaugural year). Professional Service. Dr. Maryanoff is Associate Editor of ACS Medicinal Chemistry Letters. He has served on Editorial Advisory Boards of 12 journals; for 4 years on the Medicinal Chemistry Study Section of the National Institutes of Health; for 4 years on the Advisory Board of the ACS Petroleum Research Fund; as Chairman of the 1989 Gordon Research Conference on Organic Reactions and Processes; as member of Board of Directors of the ACS Philadelphia Section; and as Chair of the Philadelphia Organic Chemists’ Club. He organized and chaired numerous symposia, at ACS national/regional meetings and an AAAS national meeting; was inaugural editor of the book series Advances in Medicinal Chemistry; and edited two special issues of J. Med. Chem., honoring

the memory of Dr. Paul Janssen (2005) and commemorating the ACS MEDI centennial (2009). Selected Bruce Maryanoff Publications: The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry,

mechanism, and selected synthetic aspects. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. Macrocyclic peptide inhibitors of serine proteases. Convergent total synthesis of cyclotheonamides A and B via

a late-stage primary amine intermediate. Study of thrombin inhibition under diverse conditions. Maryanoff, B. E.; Greco, M. N.; Zhang, H.-C.; Andrade-Gordon, P.; Kauffman, J. A.; Nicolaou, K. C.; Liu, A.; Brungs, P. H. J. Am. Chem. Soc. 1995, 117, 1225.

Synthesis of pyridine-containing macrocycles by cobalt-mediated trimerization of triply-bonded species.

Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E. J. Am. Chem. Soc. 2001, 123, 3157. Adventures in drug discovery: potent agents based on ligands for cell-surface receptors. Maryanoff, B. E. Acc.

Chem. Res. 2006, 39, 831. Collagen-related peptides: self-assembly of short, single strands into a functional biomaterial of micrometer

scale. Cejas, M. A.; Kinney, W. A.; Chen, C.; Leo, G. C.; Tounge, B. A.; Vinter, J. G.; Joshi, P. P.; Maryanoff, B. E. J. Am. Chem. Soc. 2007, 129, 2202.


6

Andrea Stierle University of Montana http://biomed.health.umt.edu/users/andreastierle "Bioprospecting in the Berkeley Pit: Extremophilic Microbes in Drug Discovery" ABSTRACT : Fungi isolated from an acid mine waste lake have proven an unexpected source of novel, bioactive metabolites. Berkeley Pit Lake is part of the largest Superfund site in North America. Despite its low pH and high metal content, it is an ideal environment for certain types of extremophiles. Fungi isolated from the surface waters to the basal sediments have been grown in liquid cultures. Bioassay-guided fractionation has directed the purification of small molecule inhibitors of enzymes associated with inflammation (caspase-1) and epithelial-mesenchymal transition (matrix-metalloproteinase-3, MMP-3). The structures of pure compounds were determined using 1D and 2D NMR, mass spectrometry and x-ray crystallography. Novel compounds were further by National Cancer Institute-Developmental Therapeutics Program,

Memorial Sloan Kettering Cancer Center and Eisai, Inc for anti-proliferative activity against specific human cancer cell lines. In these studies, particular attention has been paid to the isolation of caspase-1 and MMP-3 inhibitors. When up-regulated, MMP-3 promotes tumor cell invasion through the loss of cellular adhesion. Caspase-1 plays an important role in chronic inflammation. It is activated upon binding to the inflammasome, a multiprotein complex that plays a key role in innate immunity. Activated caspase-1 in turn activates proinflammatory cytokines. Up-

regulation of caspase-1 and concomitant chronic inflammation have been associated with leukemia, melanoma, glioblastoma, pancreatic cancers and breast cancer. Compounds isolated using this methodology have demonstrated potent activity against specific cancer cell lines. Some of these compounds will be described.

Brief Biosketch: Andrea Stierle is a natural products organic chemist who utilizes targeted bioassay guided fractionation to isolate secondary metabolites from source organisms. She earned her doctorate in Organic Chemistry from Montana State University where she discovered the first host specific toxin against the weed pest spotted knapweed and found that putative sponge metabolites can actually be produced by bacterial endosymbionts. With husband and collaborator Don Stierle she continued to study Bermudian sponge endosymbionts as sources for new bioactive agents and discovered a unique antibiotic that was also active against the AIDS virus.


7

As a Research Assistant Professor at Montana State University she discovered a fungus in the bark of the Pacific yew tree that produced paclitaxel in de novo fashion. This unique fungus – Taxomyces andreanae -‐ was named after Andrea, its discoverer.

As a Research Professor at Montana Tech, a small mining college in Butte, Montana, she and Don

began their exploration of the secondary metabolites of fungi and bacteria surviving and thriving in an abandoned acid mine waste lake. Berkeley Pit Lake is part of the largest EPA Superfund site in North America. It contains over 150 billion liters of metal sulfate rich, acidic “water” (pH 2.5) and sits at the headwaters of the Columbia River. With its low pH and high metal content, it was considered too toxic to support life. In 1995, however, Andrea began to isolate fungi and bacteria from water and sediment samples. Although conditions within the Pit Lake System were too toxic for “normal” aquatic biota, these same conditions provided an ideal environment for extremophiles which have proven to be a reservoir of bioactive secondary metabolites waiting to be discovered. The Stierle have isolated compounds with activity against non-‐small cell lung cancer, ovarian cancer, and leukemia from this collection.

As a Research Professor at the University of Montana, Andrea continues to work with Don to explore

the secondary metabolites produced by these extremophiles. They are also studying the secondary metabolites of human gut microbes and Ayurvedic plants. They are currently focusing on the isolation of small molecule inhibitors of enzyme pathways associated with inflammatory processes and epithelial mesenchymal transition. Publications from the Stierle Lab Andrea Stierle, Donald Stierle, and Kal Kelley, 2006. Berkelic Acid, A Novel Spiroketal with Highly Specific Anti-tumor Activity from an Acid-Mine Waste Fungal Extremophile. J. Org. Chem. 71: 5357-‐5360. Donald B. Stierle, Andrea A. Stierle, Briana Patacini, Kyle McIntyre, Teri Girtsman, Erin Bolstad. 2011. Berkeleyones and Related Meroterpenes from a Deep Water Acid Mine Waste Fungus that Inhibit the Production of Interleukin 1-β from Induced Inflammasomes. J. Nat. Prod. 74, 2273–2277. Andrea A. Stierle, Donald B. Stierle, Teri Girtsman. 2012. Caspase-1 Inhibitors from a Deep Water, Acid Mine Waste Extremophilic Fungus with Specific Cytotoxicity Towards Leukemia Cell Lines. J.Nat. Prod. 75, 344–350. Donald B. Stierle, Andrea A. Stierle, Teri Girtsman, Kyle McIntyre, Jesse Nichols. 2012. Caspase-1 and Caspase-1 and 3 Inhibiting Drimane Sesquiterpenoids From the Extremophilic Fungus,Penicillium solitum. J. Nat. Prod. 75, 262–266 Andrea Stierle and Donald Stierle. April, 2013. Bioprospecting in the Berkeley Pit: the Use of Signal Transduction Enzyme Inhibition Assays to Isolate Bioactive Secondary Metabolites from the Extremophilic Fungi of an Acid Mine Waste Lake. In: “Bioactive Natural Products” Atta-‐Ur-‐Rahman, Ed.; Elsevier Science Publishers: Amsterdam, pp 1-‐47.


8

Matt A. Peterson Brigham Young University

http://www.chem.byu.edu/faculty/matt-a-peterson/

"3-Fluoro-3-deazauridine: Synthesis and Evaluation of a Novel Inhibitor of Orotidylic Acid Decarboxylase. A Useful Construct for the Development of Anticancer Nucleosides." Recently we developed methods for the synthesis of a new series of potential inhibitors of cytidine triphosphate synthetase (CTP synthetase), a key enzyme involved in the de novo biosynthesis of CTP. The synthetic method involved fluorination of 3-‐deazauracil nucleosides with SelectfluorTM to give the corresponding 3,3-‐difluoro-‐3-‐deazauracil derivatives in excellent yields. Fluorination at C-‐3 locked C-‐4 of the 3,3-‐difluoro-‐3-‐deazauracil products into the keto tautomeric form, in contrast to the enol tautomeric form favored in the 3-‐deazauracil precursors. Treatment of the 3,3-‐difluorouracil products with a variety of nucleophiles (Grignards, organolithiums, Wittig reagents, etc.) gave 1,2-‐carbonyl addition products with tetrahedral geometry at the C-‐4 position. Palladium catalyzed hydrogenolysis of the 3,3-‐difluoro-‐3-‐deazauracil derivatives promoted spontaneous elimination of HF to provide 3-‐fluoro-‐3-‐deazuracil derivatives which exhibited promising anticancer activities in cell culture (IC50 = 4.4–9.6 uM). Whereas the desired biological target for these compounds had been CTP synthetase, we were surprised to discover that 3-‐fluoro-‐3-‐deazauridine inhibits orotidylic acid decarboxylase (a key enzyme involved in de novo biosynthesis of uridine). Mechanistic data demonstrating that 3-‐fluoro-‐3-‐deazauridine inhibits orotidylic acid decarboxylase rather than CTP synthetase will be presented. Biological data from the cell culture screens will also be presented. The 3-‐fluoro-‐3-‐deazauridine construct has not been evaluated in extensive SAR studies to date, thus a promising opportunity for discovery of more potent derivatives may be exploited by making appropriate modifications to its basic core structure. Brief Biosketch: M. A. Peterson , ([email protected]) BS (Chemistry), Utah State University (1987); BS (Biology), Utah State University (1987) Ph.D., University of Arizona (1992); NIH Postdoctoral Fellow, Colorado State University (1993-94)

Research in our group focuses on the chemical synthesis and biological evaluation of potential antitumor and/or antiviral compounds. Modification of naturally occurring nucleosides is a unifying feature in our research.

Matt A. Peterson Publications:

J. Balzarini, F. Gago, W. Kulik, A. B. P. van Kuilenburg, A. Karlsson, M. A. Peterson, and M. J. Robins “Introduction of a Fluorine Atom at C3 of 3-Deazauridine Shifts Its Antimetabolic Activity from Inhibition of CTP Synthetase to Inhibition of Orotidylate Decarboxylase, an Early Event in the de Novo Pyrimidine Nucleotide Biosynthesis Pathway” J. Biol. Chem. 287, 30444–30454 (2012).

J. R. Shelton, C. E. Cutler, M. S. Browning, J. Balzarini, and M. A. Peterson “Synthesis and SAR of 2ʹ,3ʹ-bis-O-substituted- N6,5'-bis-ureidoadenosine derivatives: Implications for prodrug delivery and mechanism of action.” Bioorg. Med. Chem. Lett. 22, 6067–6071 (2012).

J. R. Shelton, M. Oliveira, C. E. Cutler, J. Balzarini, and M. A. Peterson "Synthesis, SAR, and preliminary mechanistic evaluation of novel antiproliferative N6,5'-bis-ureido- and 5'-carbamoyl-N6-ureidoadenosine derivatives" Bioorg. Med. Chem. 20, 1008–1019 (2012).


9

J. R. Shelton, Scott R. Burt, and M. A. Peterson "A Broad Spectrum Anticancer Nucleoside with Selective Toxicity Against Human Colon Cancer Cells in Vitro" Bioorg. Med. Chem. Lett. 21, 1484–1487 (2011).

M. A. Peterson, M. Oliveira, M. A. Christiansen, and C. E. Cutler “Preliminary SAR Analysis of Novel AntiproliferativeN6,5'-Bis-ureidoadenosine Derivatives” Bioorg. Med. Chem. Lett. 19, 6775–6779 (2009).


10

Michael D. Mosher Chair and Professor

Department of Chemistry and Biochemistry University of Northern Colorado

http://www.unco.edu/nhs/chemistry/faculty/mosher/index.html "Acridines with potential pharmaceutical significance" Abstract Body: m-Amsacrine was first prepared more than 30 years ago. This example of the 9-aminoacridine class of antitumor agents exhibits its biological activity through the formation of a DNA-Topoisomerase II-drug ternary complex. That complex causes numerous lethal strand scissions leading to cell death. Disadvantages to the use of this class of drug as an antitumor agent exist in the high rates of hydrolysis, DNA sequence and cell specificity issues, and relatively high hepatic toxicity of the initial metabolites. Research within our laboratory into elimination of these disadvantages has resulted in evaluation of related classes of acridines. Specifically, the 9-aminomethylacridines, 9-phenylacridines, and disubstituted dibenz[c,h]acridines have been prepared and analyzed in our laboratory. The syntheses, properties, and initial assessment of biological activities for these classes of potential antitumor agents will be presented. Brief Biography: Dr. Michael Mosher currently holds the rank of Professor of Organic Chemistry and serves as the Chair of the Department of Chemistry and Biochemistry at the University of Northern Colorado in Greeley, CO. He began his education in organic chemistry as a student at Missouri Southern State College in Joplin, Missouri. After two years of background studies, he transferred to the University of Idaho to complete a B.S. in 1988. Intrigued by research in chemistry, he conducted undergraduate research projects with James Cooley (carbohydrate analysis of molasses) and Chien Wai (lanthanide chemistry). He obtained an M.S. in Chemistry under the direction of Gordon W Gribble at Dartmouth College in 1990 by working on the preparation and analysis of acridine-based bis-intercalators. In 1993, he completed his PhD in the research lab of Robert D Walkup at Texas Tech University. His doctoral research focussed on the palladium-mediated cyclizations of gamma-oxoallenes. His first position after graduation was a two-year teaching post-doc assignment at the University of Idaho (1993-1995). During that post-doc, he conducted research into the synthesis of substituted isoxazolylacridines with Nicholas Natale. In 1995, he obtained his first teaching position at the University of Nebraska at Kearney and progressed through the ranks; Assistant Professor (1995-1998), Associate Professor (1998-2004), Professor (2004-2011), Chair (2006-2011). He completed a sabbatical as a Distinguished Visiting Professor at the US Air Force Academy (2008-2009) working on the evaluation of solvochromatic properties of transition metals by NMR. In 2011, he accepted the position as Chair and Professor at the University of Northern Colorado. His current group of twelve undergraduate and three graduate students is involved in research on nitrogen-containing heterocycle synthesis and methodology. He has been a member of the ACS since 1987, served as Secretary (1998), Councilor (2004-2006; 2009-2011), and Chair (1999-2001) of the Nebraska Local Section, served as Councilor (2011-present) for the Colorado Local Section, and served as the General Chair for the 2001 Midwest Regional ACS Meeting in Lincoln, Nebraska and as the General Chair for the 2008 Midwest Regional ACS Meeting in Kearney, Nebraska. His service activities include service on the ACS Committee on Meetings & Expositions (2011-2012) and on the ACS Committee on Nomenclature, Terminology, and Symbols (2012-present). He is also a member of the International Society of Heterocyclic Chemistry (ISHC, 1995-present), the Institute for Brewing and Distilling (2014-present), Sigma Xi (1995-present), Phi Kappa Phi (2002-present), and Phi Lambda Upsilon (1988-present).


11

Publications from the Mosher Group "Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A", Mowrey, M., Mosher, M.D., Briner, W. Journal of Psychoactive Drugs, 2003, 35(3), 379-382. "Structure-Activity Relationship for the 9-(Pyridin-2'-yl)aminoacridines", Mosher, M.D., Holmes, K.L., Frost, K.S. Molecules, 2004, 9(2), 102-108. “Δ2-Isoxazolines from β,γ-Unsaturated Oximes”, Mosher, M.D.; Emmerich, L.G.; Frost, K.S.; Anderson, B.J. J. Heterocycl. Chem., 2006, 43, 535-539. "Enantioselectivity in the synthesis of 3,5-disubstituted Δ2-isoxazolines", Norman, A.L.; Mosher, M.D. Tetrahedron Lett., 2008, 49, 4153-4155. doi:10.1016/j.tetlet.2008.04.125 “Potential DNA bis-Intercalating Agents. Synthesis and Antitumor Activity of N,N'-(Methylenedi-4,1-cyclohexanediyl-bis(9-acridinamine) Isomers”, Gribble, G.W.; Mosher, M.D.; Jaycox, G.D.; Cory, M.; Fairley, T.A. Heterocycles, 2014, 88(1), 535-546. doi: 10.3987/COM-13-S(S)77


12

Todd Talley

Idaho State University

Searching for specificity: The acetylcholine binding protein as a tool for drug discovery Todd T. Talley, J. Wu, K. Ho, P. Taylor ([email protected]) BS Utah; Chuck Thompson U Mt, Ph.D. 2001 UC San Diego, post-doc Assistant Professor at Department of Biomedical and Pharmaceutical Sciences Idaho State University College of Pharmacy

Abstract Body: Since the first report of the acetylcholine binding protein (AChBP) in 2001 by Sixma and colleagues more than 60 structures have been deposited in the PDB with more than 100 still in preparation. This enormous effort reflects the intense interest within the scientific community to understand the molecular determinants of ligand recognition and specificity for ligand gated ion channels. The ligands represented within this structure set include peptide toxins from snakes and snails, naturally occurring alkaloid toxins from terrestrial and aquatic sources, neonicotinoid pesticides, known nicotinic ligands including drugs currently on the market, and novel compounds. While these structures have contributed greatly to our understanding of the system their impact is muted by the confines of using a model organism with pharmacology that is distinct from human drug targets. To address these limitations our group has begun developing AChBP chimeras that incorporate elements of the ligand recognition site from specific receptor subtypes. These constructs with pharmacology that is engineered to be similar to drug targets under consideration have already yielded a series of novel X-ray structures. Coupled with our in situ “freeze frame” click chemistry methods the constructs constitute a new platform for structure guided and template driven drug discovery.

Publications from the Talley Lab:


13

Yamauchi JG, Gomez K, Grimster N, Dufouil M, Nemecz A, Fotsing JR, Ho KY, Talley TT, Sharpless KB, Fokin VV, & Taylor P (2012) Synthesizing Selective Agonists for the alpha7 Nicotinic Receptor with in situ Click-Chemistry on Acetylcholine Binding Protein Templates. Mol Pharmacol 82(4):687-699. Rojsanga P, Boonyarat C, Utsintong M, Nemecz A, Yamauchi JG, Talley TT, Olson AJ, Matsumoto K, & Vajragupta O (2012) The effect of crebanine on memory and cognition impairment via the alpha-7 nicotinic acetylcholine receptor. Life Sci 91(3-4):107-114. Grimster NP, Stump B, Fotsing JR, Weide T, Talley TT, Yamauchi JG, Nemecz A, Kim C, Ho KY, Sharpless KB, Taylor P, Fokin VV (2012) Generation of Candidate Ligands for Nicotinic Acetylcholine Receptors via in situ Click Chemistry with a Soluble Acetylcholine Binding Protein Template. J Am Chem Soc 134(15):6732-6740. Utsintong M, Rojsanga P, Ho KY, Talley TT, Olson AJ, Matsumoto K, Vajragupta O (2012) Virtual Screening against Acetylcholine Binding Protein. J Biomol Screen 17(2):204-215. Kombo DC, Mazurov A, Tallapragada K, Hammond PS, Chewning J, Hauser TA, Vasquez-Valdivieso M, Yohannes D, Talley TT, Taylor P, and Caldwell WS (2011) Docking studies of benzylidene anabaseine interactions with alpha7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related alpha7 selective ligands. Eur J Med Chem 46(11):5625-5635.


14

Cliff Berkman Washington State University

http://organic.chem.wsu.edu/cliff-berkman/ "Enzyme Inhibitors as Platforms for Prostate Cancer Diagnostic & Therapeutic Agents" ABSTRACT: Prostate-Specific Membrane Antigen (PSMA) has been described as an 'ideal biomarker' for prostate cancer because of its restricted expression mainly to prostate cancer cells, which increases with late-stage, androgen-independent, and metastatic prostate cancer. Endothelial-expression of PSMA in the neovasculature of a variety of non-prostatic solid malignancies has raised the prospect of its use as a biomarker during angioneogenesis. As a consequence, PSMA has gained significant attention as a biomolecular target for imaging and therapeutic applications. Various chemical scaffolds have been developed as inhibitors of the enzymatic activity of PSMA, some of which have been further pursued as PSMA-targeting molecules for various diagnostic and therapeutic payloads. We have found that phosphoramidate-based peptidomimetic PSMA inhibitor scaffolds selectively and rapidly penetrate prostate tumor cells through the internalization of the PSMA enzyme-inhibitor complex first into early endosomes and then lysosomes. These findings support the development of targeted diagnostic and chemotherapeutic strategies. This presentation will cover our progress in the development of small-molecule PSMA-targeted imaging and therapeutic platforms. C. E. Berkman ([email protected]) BA Chemistry (Honors), 1986 Lake Forest College, Lake Forest, IL PhD Chemistry, 1993 Loyola University of Chicago, Chicago, IL One of major efforts is aimed at the prostate cancer enzyme-biomarker known as prostate-specific membrane antigen. Some of this technology is being advanced towards the development of marketable diagnostic and therapeutic drugs through the startup company Cancer Targeted Technology (CTT). Cliff Berkman Recent Publications: 1. Chemoaffinity Capture of Pre-Targeted Prostate Cancer Cells on Magnetic Beads. Wu, L.Y.; Liu, T.; Hopkins, M.R.; Davis, W.C.; Berkman, C.E. The Prostate 2012, 72, 1532. 2. PSMA-targeted SPECT agents: Mode of Binding effect on in vitro Performance. Nedrow-Byers, J.R.; Moore, A.L.; Ganguly, T.; Hopkins, M.R.; Fulton, M.D.; Benny, P.D.; Berkman, C.E. The Prostate. 2013, 73, 355. 3. From AR to c-MET: androgen deprivation leads to a signaling pathway switch in prostate cancer cells. Liu, T.; Mendes, D.E.; Berkman, C.E. Int. J. Oncol. 2013, 43, 1125. 4. Functional prostate-specific membrane antigen is enriched in exosomes from prostate cancer cells. Liu, T.; Mendes, D.E.; Berkman, C.E. Int. J. Oncol. 2014, 44, 918. 5. Biochemical Characterization of Prostate-Specific Membrane Antigen from Canine Prostate Carcinoma Cells. Wu, L.Y.; Johnson, J.M.*; Simmons, J.K.; Mendes, D.E.; Geruntho, J.G.; Liu, T.; Dirksen, W.P.; Rosol, T.J.; Davis, W.C.; Berkman, C.E. The Prostate, 2014, 74, 451.


15

Charles Thompson

University of Montana

http://biomed.health.umt.edu/users/charlesthompson Chemical Repurposing – Beneficial Neuroimaging Probes Derived from Toxic Organophosphates Abstract Body: Organophosphate (OP) insecticides and OP nerve agents are toxic to humans because they inactivate the biological target acetylcholinesterase (AChE). AChE breaks down the neurotransmitter, acetylcholine (ACh) and is present in most neuromuscular tissues and blood. Without functional AChE, the ACh titer increases and is neurotoxic. Both OP compound types attach to the AChE enzyme forming OP-AChE adducts that block AChE from breaking down ACh. Therefore, OP insecticides and nerve agents converge to the same anti-AChE mechanism of toxicity. This identical mode of action suggests that OPs could be modified to contain a tracer atom (OP*) to track AChE in vivo. Exposure to a reactive OP* tracers, therefore, would modify available AChE and correlate with the rate and amount of OP that enters the brain. In sum, OP* tracers introduced in vivo will react with AChE to form 'tagged' OP*-AChE adducts for which rate and quantitation measures in blood and brain can also be conducted. This presentation will introduce our background in understanding OP toxicity, and how novel, 18F-labeled OP-based, positron emission tomography (PET) tracers were derived from this knoweldge and prepared that to simulate the action of OPs in vivo so that measures of the parent OP and OP-AChE adducts can be conducted.

Brief Biosketch C.M. Thompson ([email protected]) BA Chemistry, 1978 Rutgers University, NJ MS, PhD Chemistry, 1980 & 1982: The University of California, Riverside Post-doctorals, 1982-1985: Harvard University and The University of California, Berkeley Our research effort focuses on the mechanism of action of organophosphate compounds with particular interest in the interaction with target and non-target proteins and tracking of these interactions in vivo. Knowledge of the


16

OP-protein adducts formed during exposure can aid greatly with a therapeutic course of action and with protein imaging following post-OP exposure events. Aspects of this technology are being developed as platforms for the study of chemical agent countermeasures, anti-acetylcholinesterase antidotes, and in the imaging of neurodegenerative diseases with Rio Pharmaceuticals and ATERIS Technologies. Relevant Publications: James, SL, Ahmed SK, Murphy S, Braden MR, Belabassi Y, VanBrocklin HF, Thompson CM, Gerdes JM. (2014) A Novel Fluorine-18 β-Fluoroethoxy Organophosphate Positron Emission Tomography Imaging Tracer Targeted to Central Nervous System Acetylcholinesterase. ACS Chemical Neuroscience; in press, doi: 10.1021/cn500024c. Hitt, D.M.; Belabassi, Y.; Suhy, J.; Berkman, C.E.; Thompson, C.M. (2014) Chemoenzymatic Resolution of rac-Malathion. Tetrahedron: Asymmetry 6–7, 529-533. Ahmed SK, Belabassi Y, Sankaranarayanan L, Chao C-K, Gerdes JM, Thompson CM (2013) Synthesis and anti-cholinesterase properties of novel beta- and gamma-substituted alkoxy organophosphates. Bioorg. Med. Chem. Let., 23, 2048-2051. Gerdes JM, James S, Ahmed SK, Belabassi Y, Braden MR, VanBrocklin HF, Thompson CM (2013) A Novel High Affinity F-18 Organophosphonate Tracer for CNS Acetylcholinesterase. J. Nucl. Med., 54(S2): 323. Thompson, C.M., Prins, J.M., and George, K.M. (2010) Mass spectrometric analyses of organophosphate insecticide oxon protein adducts. Environ Health Perspect. 118, 11-19.


17

Our Sponsors: ACS Division of Medicinal Chemistry (MEDI) http://www.acsmedchem.org/

College of Health Professions & Biomedical Sciences (CHPBS), University of Montana http://www.health.umt.edu/

Department of Biomedical & Pharmaceutical Sciences, University of Montana http://biomed.health.umt.edu/


18

MeD CHeM 101

http://medchem101.com/ Western Montana Clinic.

https://www.westernmontanaclinic.com/

symposium on translating chemistry into medicines · symposium on translating chemistry into...

Documents