Concise asymmetric synthesis of new enantiomeric C-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease.

Abstract

A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as β-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal β-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.

• Authors: Tessa Castellan, Virginie Garcia, Frédéric Rodriguez, Isabelle Fabing, Yevhenii Shchukin, My Lan Tran, Stéphanie Ballereau, Thierry Levade, Yves Génisson, Cécile Dehoux
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 18 Issue 39 Pg. 7852-7861 (10 14 2020) ISSN: 1477-0539 [Electronic] England
• PMID: 32975266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Gaucher Disease