Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors.

ABSTRACT: A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the

SUBMITTER: Baudoin-Dehoux C 

PROVIDER: S-EPMC6359432 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature