Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors
Kah-Yee Li,Jianbing Jiang,Martin D. Witte,Wouter W. Kallemeijn,Wilma E. Donker-Koopman,Rolf G. Boot,Jeroen D. C. Codée,Gijsbert A. van der Marel,Herman S. Overkleeft
Organic & Biomolecular Chemistry Pub Date : 08/19/2014 00:00:00 , DOI:10.1039/C4OB01611D
Abstract

The natural product, cyclophellitol and its aziridine analogue are potent mechanism-based retaining β-glucosidase inhibitors. In this paper we explore the inhibitory potency of a number of cyclophellitol analogues against the three human retaining β-glucosidases, GBA, GBA2 and GBA3. We demonstrate that N-alkyl cyclophellitol aziridine is at least equally potent in inhibiting the enzymes evaluated as its N-acyl congener, whereas the N-sulfonyl analogue is a considerably weaker inhibitor. Our results complement the literature on the inhibitory potency of cyclophellitol analogues and hold promise for the future design of more effective activity-based retaining glycosidase probes with respect to probe stability in physiological media.

Graphical abstract: Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors