Iminosugars : Their Synthesis and Therapeutic Applications for Gaucher disease

Presentation of the Compain Group Achievements(Université de Strasbourg, France)

Laura Mamani Laparra (Lebel Group)

Wednesday November 16th 2011

NH

OHHO

HO

OH

2

About Me

3

About Me

The Compain Group

4

Prof. Philippe Compain

http://www-ecpm.u-strasbg.fr/umr7509/labo_philcompain/index.htm

• Engineer Degree in Chemistry, CPE Lyon, France

• PhD with Prof. J. Goré, Univ. Lyon I, France

• Post-Doc with Prof. S. Hanessian, Univ. Montréal, Canada

• Chargé de recherche (researcher) appointment in Prof. O.

R. Martin’s group, CNRS Orléans, France

• 2008 : Full Professor Appointment at School of Chemistry,

Polymers and Materials of Strasburg, France

• 2009 : Birth of the Research Group

The Compain Group

5

Laboratory of Organic Synthesis and Bioactive Molecules

http://www-ecpm.u-strasbg.fr/umr7509/labo_philcompain/index.htm

Outline

• About Iminosugars

• Therapeutic Applications

• How to synthesize them

• The Gaucher Disease and the Pharmacological Chaperone Therapy

• Multivalency

• Conclusion6

What are Iminosugars?

7

• Structure

OHO

HO

HO OH

OHNH

HO

HO

HO OH

ORNH

HO

HO

HO OH

CH2Z

Hexoses Iminoglycosides Imino-C-glycosides

R, Z = -sugar, -lipid,-peptide, -phosphate, ...

Unstable Stable

O

OHH2N

HOHO

OH

Glucosamine

NH

OHHO

HO

OH

1-Deoxynojirimycin (DNJ)

≠

AminosugarIminosugar

P. Compain, O. R. Martin, Iminosugars: From Synthesis to Therapeutic Applications; Wiley, 2007.

About Iminosugars

8

• 1960’s : First reported syntheses of iminosugars by the groups of Paulsen,1 Jones2 and Hanessian3

• First Isolation of Nojirimycin from Streptomyces roseochromogenes4

• Historically known as potent glycosidase inhibitors5

1 Paulsen et al., ACIEE, 1962, 1, 454. Paulsen et al., ACIEE, 1962, 1, 597.2 Jones et al., J. Chem. Soc., 1962, 4699. Jones et al., Can. J. Chem., 1963, 41, 636.3 Hanessian et al., J. Org. Chem., 1963, 28, 2604. Hanessian et al., Chem. Commun., 1966, 796.4 T. Nishikawa, N. Ishida, J. Antibiotics, 1965, 18, 132-133.5 A. E. Stütz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH, 1999.

O

OHHO

HO

OH

ORO

OHHO

HO

OH

OH

Glycosidases

H2O

N

Ac

OH

OH

OH

HO

N

Ac

Jones, HanessianPaulsen

OH

OH

OH

HO

N

Ac

OH

OH

OH

HO

Jones

N

H

OHHO

OH

OHHO

Nojirimicyn

Their Biological Properties

9

O

O

O

HOHO

OH

O

O

HO

HHO

O

O

O

HO

NH2

R

H

OH

HOHO

OH

• Act as Transition State Mimics (Glycosidases)

Nitrogen atom can be protonated at physiological pH 1

• Mimicking of the positive charge of the oxocarbenium ion (TS)

• Strucural resemblance to its natural homologues

• Iminosugars are also potent inhibitors of a wide array of enzymes

1 P. Compain, O. R. Martin, Iminosugars: From Synthesis to Therapeutic Applications; Wiley, 2007.

Their Biological Properties

10

• Marketed Drugs

N

OHHO

HO

OH OH

N

OHHO

HO

OH

Glyset® (Bayer)Type II diabetes

Zavesca® (Actelion)Gaucher and Niemann Pick type C

• Iminosugars are potent inhibitors of a wide array of enzymes

Potential therapies for several diseases: diabetes, lysosomal storage disorders, viral infections, cancers…

NH O

4

OH

HOHO

OH

IC50 = 9MGlucosylceramide synthase

Gaucher disease

N

OH OH

OH

6

H

Ki = 2.2 nMhuman -glucocerebrosidase

Gaucher disease

N

OH

OH HN

H

HOHO

O13

IC50 = 38 MHL-60 cells

Anticancer activity

NH

15

OH

HOOH

HO

HIV-1 gp ligand

NH

OH

HOHO

OO

HO

OH

HOHO

OH

IC50 = 13 nMporcine kidney trehalase

type II diabetes

P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein.

How to synthesize them?

11

• Challenges

At least 4 contiguous stereogenic centers must be obtained with high stereocontrol

The piperidine or pyrrolidine ring must be generated efficiciently

Due to the high density of functional groups , the protecting groups must be

selected judiciously, especially for the endocyclic amino group

• 2 main synthetic strategies

Intramolecular cyclization

Intermolecular approach which makes use of an electrophilic iminosugar

donor• Most of the reported syntheses use carbohydrates as starting materials However, a few de novo syntheses exist

Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711.

The Intramolecular cyclization approach

12

N CH2R1

23

4

5

Iminosugar C-glycosides

O ORO

N3

LG

O

R

N3

NHR1

EWG

N3

EWG

O

N3

O

O

OR

O

NHR1

CH2RO

O

CH2R

N3

O

CH2R

NHR1

NHR1

CH2R

NHR1

LG

CH2R

LG

NHR1

CH2R

Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein.

N CH2R1

23

4

5

Iminosugar C-glycosides

O ORO

N3

LG

O

R

N3

NHR1

EWG

N3

EWG

O

N3

O

O

OR

O

NHR1

CH2RO

O

CH2R

N3

O

CH2R

NHR1

NHR1

CH2R

NHR1

LG

CH2R

LG

NHR1

CH2R

N CH2R1

23

4

5

Iminosugar C-glycosides

O ORO

N3

LG

O

R

N3NHR1

EWG

N3

EWG

O

N3

O

O

OR

O

NHR1

CH2RO

O

CH2R

N3

O

CH2R

NHR1

NHR1

CH2R

NHR1

LG

CH2R

LG

NHR1

CH2R

N CH2R1

23

4

5

Iminosugar C-glycosides

O ORO

N3

LG

O

R

N3

NHR1

EWG

N3

EWG

O

N3

O

O

OR

O

NHR1

CH2RO

O

CH2R

N3

O

CH2R

NHR1

NHR1

CH2R

NHR1

LG

CH2R

LG

NHR1

CH2R

The Intramolecular cyclization approach

13Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein.

• Reductive Amination

The most popular reaction to form imino-C-glycosides to date

Allows the generation of one or two stereogenic centers

Compatible with a broad array of functional groups

R1 R2

O

H2NRR1 R2

NHR Reduction

R1 * R2

RHN H

• Several methods exist (intra- & intermolecular)

• Using various intermediates as starting materials (free and protected amines,

azides as nitrogen containing moieties)

The Intramolecular cyclization approach

14

• Double Reductive Amination

Formation of C5-N and C1-N bonds in a single synthetic step

Gives almost exclusively the β-diastereomer

O

O

OBn

deBnO

BnO

[LiCH2OMOM]

THF, - 78 °C70 %

OOBn

BnOBnO

BnOOMOM

OH

LAH

THFOH

OBn

BnOBnO

BnO

OH

OMOM

TFAA

DMSO-CH2Cl2Et3N

OOBn

BnOBnO

BnO

O

OMOM

NH4+HCO2

-

NaBH3CN

MeOHNH

OBn

BnOBnO

BnO

OMOMde > 98 %

50 % (2 steps)

97 %

O. M. Saavedra, O. R. Martin, J. Org. Chem., 1996, 61, 6987.J. Van Boom, et al., Eur. J. Org. Chem., 1999, 1185.

OOBn

O

BnO

BnO

BnO

3 stepsO

OBnBnO

BnOBnO

O

O

BnO OMeOBn

OBn

NH4+HCO2

-

NaBH3CN

CH2Cl2/MeOH

NH O

BnO OMeOBn

OBnBnO

OBn

OBn

BnO

54-61 % 58-63 % de > 98 %

The Intramolecular cyclization approach

15

• Azide-containing substrates

G. W. J. Fleet, et al., Tetrahedron Lett. 1989, 30, 4439.

Reduction of the azide and formation of C-N bond are performed in a single step

OHO

OH

O

O O

4 steps

53 %

O

N3

O O

Me

OH

TBSO

O

N3

O O

R

OH

TBSO

1) H2, PtO22) TFA/H2O

47%

1) H2, PtO22) TFA/H2O

73-82 %

N NHMeOH

OH

OH

HO HHO

HO OH

HOR

de > 98 % de > 98 %

R = Me, Et, Ph

The Intramolecular cyclization approach

16

• Azide-containing substrates

G. W. J. Fleet, et al., Tetrahedron Lett. 1989, 30, 4439.A. Fernandez-Mayoralas, J. Org. Chem., 2006, 71, 6258.

Reduction of the azide and formation of C-N bond are performed in a single step

O OH

HO

Me

OH

OH

5 steps

30 %

OMeN3

O O

OH

OMOMH2, Pd/C

NH N

MeHOO

O OMOM

OH

MeO

OMOMOH

46 % 44 %L-Rhamnose O

OEt

O

EtO

OH

OH

5 steps12 %

O O

Ph

CHO

N3

O

Me

OH

L-prolineO O

Ph

N3

Me

OOH

OH

O

Me

OH

D-proline65 %40 %

O O

Ph

N3

Me

OOH

OHH2, Pd/C H2, Pd/C

MeOH/HCl(45 psi)

MeOH/HCl(45 psi)

NH

HO

OH

MeHO

OH

: 1.4/1

NHMe

: 1/6

HOOH

HOHO

The Intramolecular cyclization approach

17

• From δ-amino ketones

G. Godin, P. Compain, G. Masson, O. R. Martin, J. Org. Chem., 2002, 67, 6960.G. Masson, P. Compain, O. R. Martin, Org. Lett., 2000, 2, 2971.

O

OO

OO

OH

O

OBnBnN

OO

OBn

7 steps

RMgBr or RLi

Et2O60-90 %

O

OBn

OO

OBnR

BnHNH

de > 90 %

1) TFA/H2O (9/1)2) NaBH3CNAcOH, MeOH

3) Ac2O, Py

53-75 %

NH

RAcOBnO

AcO

OBn

de > 98 %

RMgBr or RLi

BF3.Et2OEt2O

69-72 %

O

OBn

OO

OBnR

HBnHN

de > 98 %

1) H2, Pd/C, H+

2) TFA/H2O (9/1)

3) NaBH3CNAcOH, MeOH

NH

HOHO

HO

OHde > 98 %

R

60-62 %

R = alkyl

R = alkyl, vinyl, allyl

80 %

The Intramolecular cyclization approach

18

• From δ-amino ketones

L. Cipolla, B. La Ferla, F. Peri, F. Nicotra, Chem. Commun., 2000, 1289.L. Cipolla, R. M. Fernandes, M. Gregori, C. Airoldi, F. Nicotra, Carbohydr. Res., 342, 1813.B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra, Eur. J. Org. Chem., 2004, 2451.

O

OBnBnO

BnO

OBn

OH

1) BnNH22) RMgBr

3) FmocCl

50-57 %

OH

BnOBnO

BnO

OBn

R

NBnFmoc

de 90 % (R = allyl)de 70 % (R = vinyl)

1) PCC2) Fmoc Deprotection

3) NaBH(OAc)3AcOH

NBn

BnOBnO

BnO

OBn

Rde 90 % (R = allyl)de 60 % (R = vinyl)63-70 %

O O

O

OBnBnO

OBn

Ph3P CHCO2R

OBn

OBn

OBn

CO2R

O

OR'NH2

52-80 %R' = allyl; Bn, butyl

R = Et, Bn

OBn

OBn

OBn

CO2R

O

O

NHR'

de 20-26 %

5 steps

OBn

OBn

OBn

CO2R

O NHR'

de 20-26 %

TBDPSO

NaBH(OAc)3

AcOH

40-98 %

N

R'

OBnBnO

OBn

TBDPSO CO2R

trans/cis ratio 100/0 to 20/80

The Intramolecular cyclization approach

19

• Intramolecular SN2 reaction

B. A. Johns, C. R. Johnson, Tetrahedron Lett., 1998, 39, 749.L. Cipolla, L. Lay, F. Nicotra, C. Pangrazio, L. Panza, Tetrahedron, 1995, 51, 4679.

Inversion of configuration D-series sugar L-series Imino-C-glycosides

NHZ

TBSO

OO

OO

OTBS

NHZ8

1) O32) NaBH4

3) TBSCl4) MsCl, TEA

OTBSNHZ

TBSO

OO

OTBS

OO

OTBS

NHZMsO

OMS5

NZ

OO

TBSO

N

OO

Z

OTBS

OTBS

OTBS5

t-BuOK

95 %

48 % de > 98 %

O

OBnBnO

BnO

OBn

OH

BnNH2O

OBnBnO

BnO

OBn

NHBn

MgBr BnO

OBn

NHBnOBn

OBn

OH

60 % (2 steps)de 90 %

1) Tf2O, Py

2) H2, Pd/CHCl 2M

52 %

NOHHO

OH OH

H

The Intramolecular cyclization approach

20

• Electrophile-induced cyclization of aminoalkenes

P. S. Liu, J. Org. Chem., 1987, 52, 4717.O. R. Martin, L. Liu, F. Yang, Tetrahedron Lett., 1996, 37, 1991.J.-Y. Goujon, D. Gueyrard, P. Compain, O. R. Martin, K. Ikeda, A. Kato, N. Asano, Bioorg. Med. Chem., 2005, 13, 2313.

OBnOBnO

OBn

OBn

OH

3 steps

60 %

BnOBnO

OBn

BnON

OH1) LAH

2) CbzClK2CO3

BnOBnO

OBn

BnONHZ 1) Hg(OAc)2

2) O2NaBH4

67 % 71 %

NZBnOBnO

BnO

OBn

OHde > 98 %

OAcOAcO

AcO

OAc

Br

Hg(CN)2

79 %

NZBnOBnO

BnO

OBn

OOAcO

AcOAcO

OAc

OBn

OBnNHBn

BnOBnO

OBn

BnOBnO

NH2

NIS

80 %

NBnI

OBnBnOH

BnO

NHBnO

BnO

OBn

NIS

78 %

I

de > 98 %

de 70 %

The Intramolecular cyclization approach

21

• Hetero-Michael Reaction

I. J. McAlpine, R. W. Armstrong, Tetrahedron Lett., 2000, 41, 1849.

O

OO

O

O

O

NHZ 9 steps

17 %

O

OTBSMe

TBSO NHZ 1) pTsOH

2) H2, Pd/C

NH

TBSO

MeO

OTBS

de > 98 %

74 %

The Electrophilic Iminosugar Donor approach

22

N CH2R

NZ

F

NZ

OR

NZ

SO3H

NO

N

NCl

NFmoc

NZ

Bt Bt

1

23

4

5

Imino-C-glycosides

Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein.

The Electrophilic Iminosugar Donor approach

23

T. Fuchss, H. Streicher, R. R. Schmidt, Liebigs Ann. Recl., 1997, 1315.C. R. Johnson, A. Golebiowski, H. Sundram, M. W. Miller, R. L. Dwaihy, Tetrahedron Lett., 1995, 36, 653.I. Ojima, E. S. Vidal, J. Org. Chem., 1998, 63, 7999.

• Nucleophilic Substitution

O

OOHHO

HO

OH6 steps

28 %

N

OAcAcO

AcO

OAc

OMeCBz N

OAcAcO

AcO

OAc

SPhCBz

PhS-TMSTMSOTf

83 %

DASTNBS

90 %

N

OAcAcO

AcO

OAc

FCBz

BF3.OEt2RSiMe3

51-95 %

N

AcOAcO

AcO

OAcCBz

Rde 33-100 %R = CN, Allyl, Propynyl

OH

NHCbz

O

O

Br via microbialoxidation

4 steps~ 24 %

5 steps

48 %

N

Cbz

OO

OTBS

OMeTBSO

BF3.OEt2allylTMS

94 %

N

Cbz

OO

OTBS

TBSOde > 98 %

The Electrophilic Iminosugar Donor approach

24

M. A. T. Maughan, I. G. Davies, T. D. W. Claridge, S. Courtney, P. Hay, B. G. Davis, Angew. Chem., Int. Ed., 2003, 42, 3788.A. Peer, A. Vasella, Helv. Chim. Acta, 1999, 82, 1044.

• Addition to endocyclic C=N bond

O O

OBnBnO

OBn

BnO 5 steps

65 %

HN

OBnBnO

OBn

BnO 1) NCS

2) DBU

N

OBnBnO

OBn

BnO

EtMgBrHN

OBnBnO

OBn

BnO

44 % (3 steps)

1) NCS2) LiTMP

N

OBnBnO

OBn

BnO1) LAH

2) H2, Pd/C

24 %(4 steps)

HN

OHHO

OH

HO

O

OH

HOHO

OHOH

14 steps

~ 8 %

NOBn

OBn

OBn

Me

O 1) TMSCNAlMe2Cl

2) TsOH

86 %

N

CN

OBnOBnBnO

MeH

de 89 %

H2, Pd/CHCl

75 %N OH

OHHO

MeH

NH3

Cl

The Electrophilic Iminosugar Donor approach

25

P. J. Dransfield, P. M. Gore, M. Shipman, A. M. Z. Slawin, Chem. Commun., 2002, 150.P. J. Dransfield, P. M. Gore , I. Prokes, M. Shipman, A. M. Z. Slawin, Org. Biomol. Chem., 2003, 1, 2723.

• From Iminoglucals

O

OH

HO

OH

11 steps

10 %

N

OAc

AcO

OAc FmocNu, Lewis Acid

63-80 %

N

AcO

OAc Fmoc

R

de 24-72 %

Conditions

allylTMS, BF3.Et2OEt2Zn, BF3.Et2OH2C=C(OSiMe3)Ph, BF3.Et2OMethylenecyclohexane, SnBr4

79 :2167 :3362 :3886 :14

R = Et1) OsO4, NMO2) Ac2O, Py3) piperidine 43 %

N

AcO

OAc H

R

OAc

OAc

Iminosugar C-glycosides building blocks

26G. Godin, P. Compain, O. R. Martin, Org. Lett., 2003, 5, 3269.G. Godin, P. Compain, O. R. Martin, Synlett, 2003, 2065.

• Imino-C-glycosides bearing a key functional group

O

OO

OO

OH

14 steps

30 %

NZ

AcO

AcOBnO

OBnR

Z = Troc, CHO

Grubbs II Catalyst NZ

AcO

AcOBnO

OBn

R

R = -CO2Et

- SO2Ph

-P(O)(OEt)2

BrO

O

N

O

Boc

NAcOOBn

OAcOBnZ

45-96 %

(2-5 equiv.)

(5-20 mol%)

Alkene Cross Metathesis

Rapid, simple and powerful method to generate iminosugar C-glycosides with a great degree of diversity in the aglycon moieties

Iterative Functionalization of Unactivated C-H Bonds in Piperidines

27S. Toumieux, P. Compain, O. R. Martin, J. Org. Chem., 2008, 73, 2155.

By Intramolecular Rhodium(II)-Catalyzed C-H Amination

The Strategy

"The sulfamoyloxymethyl group is used several times as a « molecular activating arm » allowing the formation of C-C, C-N or C=C double bonds"

Attractive strategy for the total synthesis of polyfunctionalized piperidines

Iterative Functionalization of Unactivated C-H Bonds in Piperidines

28S. Toumieux, P. Compain, O. R. Martin, J. Org. Chem., 2008, 73, 2155.

N

Ts OSO2NH2

PhI(OAc)2MgO

Rh2(OAc)4 cat.

CH2Cl2, 40°C

67 %

N

TsHNS OO

O

AcOH

60 °C N

Ts OSO2NH2

1) I2, MeONaMeOH, - 78 °C

N

Ts OSO2NH2

MeO2) DBUToluene, 60 °C

73 % (2 steps)

PhI(OAc)2MgO

Rh2(esp)2 cat.

CH2Cl2, 40°C

87 %

N

Ts

MeO

HN

S

O

O

O

DihydroxylationEpoxydationDiels-Alder

NucleophilicAddition

NucleophilicAddition

N

Ts

MeO

HN

S

O

O

O

AllylTMSSnCl4

CH2Cl2, - 78 °C N

Ts

HN

S

O

O

O

de 61%90 %

Boc2ODMAP, Py

CH2Cl2, 0 °C

70 %

N

Ts

NS

O

O

O

Boc

KOAc

DMF, 40 °C

91 %

N

Ts

NHBoc

OAc

N

Ts

MeO

HN

S

O

O

O

Et3SiHSnCl4

CH2Cl2, - 78 °C

99 %

N

Ts

HN

S

O

O

O

Ac2ODMAP, tBuOK

CH2Cl2, - 20 °C N

Ts

NS

O

O

O

AcO

OAc

N

Ts

NS

O

O

O

Ac

98 %

1) OsO4, NMOAcetone/H2O 9:1

rt

2) Ac2O, DMAPCH2Cl2, rt

66 % (2 steps)

Ac

The Gaucher Disease

29

• Lysosomal Storage Disorder (LSD)

(Lysosomes = cellular organelles specialized in the enzymatic digestion of cellular debris)

Group of genetically inherited disorders (> 60) often caused by the deficiency in the activity of a particular lysosomal enzyme

J. M. Benito, J. M. García Fernández, C. Ortiz Mellet, Expert Opin. Ther. Patents, 2011, 21 (6), 885.

Deficiency of one of these enzymes causes the accumulation of undegraded substrates in the cells

• Gaucher Disease (also known as Glucosylceramidose)

The most prevalent LSD (1 in 20,000 live births in developed countries)But 1 in 500 births in the Ashkenazi Jew community

Deficient Activity of β-Glucocerebrosidase, the enzyme responsible for the degradation of glucosylceramide

The Gaucher Disease

30

The Gaucher Disease

31

OO

OH

HOHO

OH

HN

OH

C13H27

O

C17H35

Glucosylceramide

-Gluco-cerebrosidase

Glucosylceramidesynthase

HO

HN

OH

C13H27

O

C17H35

Ceramide

Deficiency of the enzyme often related to abnormal protein folding in endoplasmic reticulum (caused by gene mutations)

However, some residual activity remains

Severity of symptoms depends on residual activity of the enzyme

3 Clinical Gaucher Disease VariantsType 1 : Non-neuronophatic, the most commonType 2 : Neuronophatic, Lethal form (1 or 2 years)Type 3 : Neuronophatic, Slower progression

The Gaucher Disease

32

OO

OH

HOHO

OH

HN

OH

C13H27

O

C17H35

Glucosylceramide

-Gluco-cerebrosidase

Glucosylceramidesynthase

HO

HN

OH

C13H27

O

C17H35

Ceramide

• Currently, there are 3 therapeutic approaches

Enzyme Replacement Therapy (ERT)

Cerezyme® very efficient for type 1 disease (cannot cross blood-brain barrier)But very costly ($ 100,000 – 200,000 per year)

Substrate Reduction Therapy (SRT)

N

OH

HOHO

OH

Zavesca®

Zavesca® Inhibition of Glucosylceramide synthaseOnly for type 1 patients who have medical contraindications to ERT

Not enzyme selective enough (causing secondary effects)

J. M. Benito, J. M. García Fernández, C. Ortiz Mellet, Expert Opin. Ther. Patents, 2011, 21 (6), 885.

The Pharmacological Chaperone Therapy

33J. M. Benito, J. M. García Fernández, C. Ortiz Mellet, Expert Opin. Ther. Patents, 2011, 21 (6), 885.

The Pharmacological Chaperone Therapy

34

• Counterintuitive concept Using inhibitors to recover enzyme activity

Ability of a small organic molecule, a reversible competitive inhibitor, to

stabilize or modify the folding of the deficient enzymes

When chaperones are present at sub-inhibitory concentrations, proteins will not be

degraded by the « quality-control » system of the endoplasmic reticulum

The Pharmacological Chaperone Therapy

35P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K. Ikeda, N. Asano, ChemBioChem, 2006, 7, 1356.

N

OHHO

HO

OH

Zavesca®

N

OHHO

HO

OH

6

Ki (nM)(Human Glucocerebrosidase)

116 000 300

NH

HOHO

HO

OH

2

110 000

NH

HOHO

HO

OH

7

200

NHOH

OHOH

6

2.2

NHOH

OHOH

6

10 nm

$

Effect of Multivalency on Glycosidase Inhibition

36C. R. Bertozzi, L. L. Kiessling, Science, 2001, 291, 2357.J. E. Gestwicki, C. W. Cairo, L. E. Strong, K. A. Oetjen, L. L Kiessling, J. Am. Chem. Soc., 2002, 124, 14922.

• Multivalency plays a great role in sugar-lectine interactions

Allowing an important gain in affinity between them

• Can be explained by several mechanisms

Effect of Multivalency on Glycosidase Inhibition

37

• First Significative Result!

R

OO

O

O

O

O

O

O

O

O O

O

O

OO

O

O

O

O

O

O

OO O

NN

N

NNN

N NN

NN

N

N

N NN N

N

NNN

NN N

NNN

NN

N

N

NN NN

N

R

R

R

R

R

R

R

R

R

R

R

N

OHHO

HO

OH8

R =

N

OHHO

HO

OHN

NNC3H7

5

6Monovalent analogue

P. Compain, C. Decroocq, J. Iehl, M. Holler, D. Hazelard, T. Mena Barrágan, C. Ortiz Mellet, J.-F. Nierengarten, Angew. Chem., Int. Ed., 2010, 49, 5753.

Effect of Multivalency on Glycosidase Inhibition

38

• My 6-month Master Research ProjectNH

OH OH

OH

1-C-nonyl-1,5-dideoxy-1,5-imino-D-xylitol

Synthesis of Azide-Armed α-1-C-Alkyl-imino-D-xylitol

Derivatives as Key Building Blocks for the Preparation

of Iminosugar Click Conjugates

N N3

OHH

OHOH

N N3

OHH

OHOH

OO

O

O

O

O

O

O

O

O O

O

O

OO

O

O

O

O

O

O

OO O

+

1,3-Dipolar Cycloaddition Dodecavalent

Iminosugar Ball

Effect of Multivalency on Glycosidase Inhibition

39C. Decroocq, L. Mamani Laparra, D. Rodríguez-Lucena, P. Compain, J. Carbohydr. Chem., 2011, in press.

O

OHHO

HOOH

O

BnOBnO

BnOOH

3

3 steps

51 %

O

BnOBnO

BnONHNAP

NH2.HCl

DMSO, 60-70°C, 16h

BrMg

6

HO

OBn

OBn

OBn

NHNAP

THF, 0°C -> t.a., 15h

NNAP

BnO

MsCl, 2,5 éq

Py, MS 4 Å100°C, 4h 7b

BnOBnO

NNAP

BnO

7a

BnOBnO

76 %13%

Et3N

5

70 %(2 steps) de 60 %

NNAP

BnO

7b

BnOBnO

DDQ, CH2Cl2/H2O

0 °C to rt

NH

BnO

BnOBnO

86 %

Boc2O, Et3N

CH2Cl2, 0 °C to rt

97 %

NBoc

BnO

BnOBnO

OTsGrubbs-Hoveyda Cat.

CH2Cl2, 40 °C

67 %

NBoc

BnO

BnOBnO

OTs

1) H2, Pd/C, HCl 2MTHF/MeOH, rt

88 %

2) NaN3, DMSO, rtQuant.

3) TFA/H2O, rt73 %

HN

OH

OHHO

N35

10 11

1215

Conclusion

40

• In the last 30 years, the rate of discoveries in the field has increased dramatically!

• Several potential therapeutic applications have been found and some active

compounds are already on the market or in clinical trials

• Plenty of different synthetic strategies exist to make iminosugars

The synthesis and study of imino-C-glycosides is quite a young discipline

There is still place for improvements and new ideas!

• Very promising results for the Gaucher Disease therapy

• First significative results for multivalency effect on glycosidase inhibition