Iminosugars : Their Synthesis and Therapeutic Applications for Gaucher disease

1
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

2
About Me
3
About Me
4
The Compain Group
Prof. Philippe Compain

• 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. Martins group, CNRS Orléans, France
• 2008 Full Professor Appointment at School of
  Chemistry, Polymers and Materials of Strasburg,
  France
• 2009 Birth of the Research Group

http//www-ecpm.u-strasbg.fr/umr7509/labo_philcomp
ain/index.htm
5
The Compain Group
Laboratory of Organic Synthesis and Bioactive
Molecules
http//www-ecpm.u-strasbg.fr/umr7509/labo_philcomp
ain/index.htm
6
Outline

• About Iminosugars
• Therapeutic Applications
• How to synthesize them
• The Gaucher Disease and the Pharmacological
  Chaperone Therapy
• Multivalency
• Conclusion

7
What are Iminosugars?

• Structure

?
Aminosugar
Iminosugar
P. Compain, O. R. Martin, Iminosugars From
Synthesis to Therapeutic Applications Wiley,
2007.
8
About Iminosugars

• 1960s 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.
9
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.
10
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, cancers
Glyset (Bayer) Type II diabetes
Zavesca (Actelion) Gaucher and Niemann Pick type
C
P. Compain, V. Chagnault, O. R. Martin,
Tetrahedron Asymmetry, 2009, 20, 672-711. and
refs therein.
11
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.
12
The Intramolecular cyclization approach
Review P. Compain, V. Chagnault, O. R. Martin,
Tetrahedron Asymmetry, 2009, 20, 672-711. and
refs therein.
13
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.
14
The Intramolecular cyclization approach

• Double Reductive Amination

Formation of C5-N and C1-N bonds in a single
synthetic step Gives almost exclusively the
ß-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.
16
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.
17
The Intramolecular cyclization approach

• From d-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 d-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.
20
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. J.-Y. Goujon, D. Gueyrard, P. Compain,
O. R. Martin, K. Ikeda, A. Kato, N. Asano,
Bioorg. Med. Chem., 2005, 13, 2313.
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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.
23
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 CN 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 CC double bonds"
Attractive strategy for the total synthesis of
polyfunctionalized piperidines
S. Toumieux, P. Compain, O. R. Martin, J. Org.
Chem., 2008, 73, 2155.
28
Iterative Functionalization of Unactivated C-H
Bonds in Piperidines
S. Toumieux, P. Compain, O. R. Martin, J. Org.
Chem., 2008, 73, 2155.
29
The Gaucher Disease

• Lysosomal Storage Disorder (LSD)

Group of genetically inherited disorders (gt 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 ß-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.
30
The Gaucher Disease
31
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
32
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.
33
The Pharmacological Chaperone Therapy
J. M. Benito, J. M. García Fernández, C. Ortiz
Mellet, Expert Opin. Ther. Patents, 2011, 21 (6),
885.
34
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.
36
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.
38
Effect of Multivalency on Glycosidase Inhibition

• My 6-month Master Research Project

Synthesis of Azide-Armed a-1-C-Alkyl-imino-D-xylit
ol 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.
40
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!