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

著者 Baudoin-Dehoux C , Castellan T , Rodriguez F , Rives A , Stauffert F , Garcia V , Levade T , Compain P , Génisson Y
Molecules.2019 Jan 19 ; 24(2):.
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A series of simple -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 -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 piperidine ring of the compound and its analogous 2--heptyl DIX were similar to that of isofagomine. Furthermore, compound promoted mutant GBA enhancements over 3-fold equivalent to that of the related -Hept DIX belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.
PMID: 30669468 [PubMed - in process]
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