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

Tessa Castellan (1) , Virginie Garcia (2) , Frédéric Rodriguez (1) , Isabelle Fabing (1) , Yevhenii Shchukin (1) , My Lan Tran (1) , Stéphanie Ballereau (1) , Thierry Levade (2) , Yves Génisson (1) , Cécile Baudoin-Dehoux (1)

1 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
2 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole

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.

Domaines: Chimie

Tessa Castellan, Virginie Garcia, Frédéric Rodriguez, Isabelle Fabing, Yevhenii Shchukin, et al.. Concise asymmetric synthesis of new enantiomeric C -alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease. Organic & Biomolecular Chemistry, 2020, 18, pp.7852-7861. ⟨10.1039/D0OB01522A⟩. ⟨hal-02966892⟩