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
About Me
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About Me
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The Compain Group
Prof. Philippe Compain
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Engineer Degree in Chemistry, CPE Lyon, France
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PhD with Prof. J. Goré, Univ. Lyon I, France
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Post-Doc with Prof. S. Hanessian, Univ. Montréal, Canada
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Chargé de recherche (researcher) appointment in Prof.
O. R. Martin’s group, CNRS Orléans, France
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2008 : Full Professor Appointment at School of
Chemistry, Polymers and Materials of Strasburg, France
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2009 : Birth of the Research Group
http://www-ecpm.u-strasbg.fr/umr7509/labo_philcompain/index.htm
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The Compain Group
Laboratory of Organic Synthesis and Bioactive Molecules
http://www-ecpm.u-strasbg.fr/umr7509/labo_philcompain/index.htm
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Outline
• About Iminosugars
• Therapeutic Applications
• How to synthesize them
• The Gaucher Disease and the Pharmacological
Chaperone Therapy
• Multivalency
• Conclusion
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What are Iminosugars?
• Structure
≠
Iminosugar
Aminosugar
P. Compain, O. R. Martin, Iminosugars: From Synthesis to Therapeutic Applications; Wiley, 2007.
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About Iminosugars
• 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.
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.
2
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Their Biological Properties
• 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.
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Their Biological Properties
• Iminosugars are potent inhibitors of a wide array of enzymes
• Marketed Drugs
Potential therapies for several diseases: diabetes, lysosomal storage
disorders, viral
infections,
Glyset®
(Bayer) cancers…Zavesca® (Actelion)
Type II diabetes
Gaucher and Niemann Pick type C
P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein.
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How to synthesize them?
• 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.
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The Intramolecular cyclization approach
Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein. 12
The Intramolecular cyclization approach
• Reductive Amination
Allows the generation of one or two stereogenic centers
Compatible with a broad array of functional groups
The most popular reaction to form imino-C-glycosides to date
• Several methods exist (intra- & intermolecular)
• Using various intermediates as starting materials (free and protected amines,
azides as nitrogen containing moieties)
Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein. 13
The Intramolecular cyclization approach
• Double Reductive Amination
Formation of C5-N and C1-N bonds in a single synthetic step
Gives almost exclusively the β-diastereomer
O. M. Saavedra, O. R. Martin, J. Org. Chem., 1996, 61, 6987.
J. Van Boom, et al., Eur. J. Org. Chem., 1999, 1185.
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The Intramolecular cyclization approach
• Azide-containing substrates
 Reduction of the azide and formation of C-N bond are performed in a single step
G. W. J. Fleet, et al., Tetrahedron Lett. 1989, 30, 4439.
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The Intramolecular cyclization approach
• Azide-containing substrates
 Reduction of the azide and formation of C-N bond are performed in a single step
G. W. J. Fleet, et al., Tetrahedron Lett. 1989, 30, 4439.
A. Fernandez-Mayoralas, J. Org. Chem., 2006, 71, 6258.
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The Intramolecular cyclization approach
• 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.
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The Intramolecular cyclization approach
• 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.
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The Intramolecular cyclization approach
• Intramolecular SN2 reaction
Inversion of configuration
D-series sugar
L-series Imino-C-glycosides
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.
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The Intramolecular cyclization approach
• 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.
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J.-Y. Goujon, D. Gueyrard, P. Compain, O. R. Martin, K. Ikeda, A. Kato, N. Asano, Bioorg. Med. Chem., 2005, 13, 2313.
The Intramolecular cyclization approach
• Hetero-Michael Reaction
I. J. McAlpine, R. W. Armstrong, Tetrahedron Lett., 2000, 41, 1849.
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The Electrophilic Iminosugar Donor approach
Review: P. Compain, V. Chagnault, O. R. Martin, Tetrahedron Asymmetry, 2009, 20, 672-711. and refs therein. 22
The Electrophilic Iminosugar Donor approach
• Nucleophilic Substitution
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.
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The Electrophilic Iminosugar Donor approach
• Addition to endocyclic C=N bond
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.
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The Electrophilic Iminosugar Donor approach
• From Iminoglucals
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.
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Iminosugar C-glycosides building blocks
• Imino-C-glycosides bearing a key functional group
Alkene Cross Metathesis
Rapid, simple and powerful method to generate iminosugar C-glycosides with a
great degree of diversity in the aglycon moieties
G. Godin, P. Compain, O. R. Martin, Org. Lett., 2003, 5, 3269.
G. Godin, P. Compain, O. R. Martin, Synlett, 2003, 2065.
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Iterative Functionalization of Unactivated C-H
Bonds in Piperidines
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
S. Toumieux, P. Compain, O. R. Martin, J. Org. Chem., 2008, 73, 2155.
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Iterative Functionalization of Unactivated C-H
Bonds in Piperidines
S. Toumieux, P. Compain, O. R. Martin, J. Org. Chem., 2008, 73, 2155.
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The Gaucher Disease
• Lysosomal Storage Disorder (LSD)
Group of genetically inherited disorders (> 60) often caused by the deficiency in the
activity of a particular lysosomal enzyme
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
(Lysosomes = cellular organelles specialized in the enzymatic digestion of cellular debris)
J. M. Benito, J. M. García Fernández, C. Ortiz Mellet, Expert Opin. Ther. Patents, 2011, 21 (6), 885.
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The Gaucher Disease
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The Gaucher Disease
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 Variants
Type 1 : Non-neuronophatic, the most common
Type 2 : Neuronophatic, Lethal form (1 or 2 years)
Type 3 : Neuronophatic, Slower progression
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The Gaucher Disease
• 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)
Zavesca®
Inhibition of Glucosylceramide synthase
Only 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.
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The Pharmacological Chaperone Therapy
J. M. Benito, J. M. García Fernández, C. Ortiz Mellet, Expert Opin. Ther. Patents, 2011, 21 (6), 885.
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The Pharmacological Chaperone Therapy
• 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
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The Pharmacological Chaperone Therapy
$
10 nm
P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K. Ikeda, N. Asano, ChemBioChem, 2006, 7, 1356.
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Effect of Multivalency on Glycosidase
Inhibition
• Multivalency plays a great role in sugar-lectine interactions
Allowing an important gain in affinity between them
• Can be explained by several mechanisms
C. 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.
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Effect of Multivalency on Glycosidase
Inhibition
• First Significative Result!
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.
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Effect of Multivalency on Glycosidase
Inhibition
• My 6-month Master Research Project
Synthesis of Azide-Armed α-1-C-Alkyl-imino-D-xylitol
Derivatives as Key Building Blocks for the Preparation
of Iminosugar Click Conjugates
+
1,3-Dipolar
Cycloaddition
Dodecavalent
Iminosugar
Ball
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Effect of Multivalency on Glycosidase
Inhibition
C. Decroocq, L. Mamani Laparra, D. Rodríguez-Lucena, P. Compain, J. Carbohydr. Chem., 2011, in press.
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Conclusion
• 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
• Very promising results for the Gaucher Disease therapy
• First significative results for multivalency effect on glycosidase inhibition
The synthesis and study of imino-C-glycosides is quite a young
discipline
There is still place for improvements and new ideas!
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