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Synlett 2014; 25(09): 1215-1240
DOI: 10.1055/s-0033-1340822
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© Georg Thieme Verlag Stuttgart · New York

Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

Philippe Compain*
b   Institut Universitaire de France, 103 Boulevard Saint-Michel, 75005 Paris, France
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Publication History

Received: 03 December 2013

Accepted after revision: 08 January 2014

Publication Date:
14 March 2014 (online)

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Abstract

This account describes our efforts aimed toward the discovery of original glycomimetics that target protein misfolding to fight rare diseases, with a focus on cystic fibrosis and Gaucher disease. The pursuit of this goal has led to promising leads and strategies, with the first description of a multivalent effect for correcting protein-folding defects in cells, and has also driven unexpected progress in synthetic methodology.

1 Introduction

2 The Therapeutic Targets: Challenges and Stakes

2.1 Glycosphingolipid Lysosomal Storage Disorders

2.2 Cystic Fibrosis

3 Synthetic Targets Met, Potent Leads Gained

3.1 Synthetic Targets Met

3.2 A First Detour via a Substrate Reduction Therapy Approach

3.3 Potent Leads Gained

4 Synthetic Targets Missed, Synthetic Progress Gained

4.1 A New Domino Reaction

4.2 Extending the Scope of C–H Amination

4.3 A New Versatile Amino Protecting Group

5 Multivalency: A New and Promising Approach

5.1 How It Began

5.2 Gaucher Disease

5.3 Cystic Fibrosis

6 Conclusion

Key words

carbohydrates - tandem reactions - C–H functionalization - multivalency - glycosidases