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 piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.
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Authors | Cécile Baudoin-Dehoux, Tessa Castellan, Frédéric Rodriguez, Arnaud Rives, Fabien Stauffert, Virginie Garcia, Thierry Levade, Philippe Compain, Yves Génisson |
Journal | Molecules (Basel, Switzerland)
(Molecules)
Vol. 24
Issue 2
(Jan 19 2019)
ISSN: 1420-3049 [Electronic] Switzerland |
PMID | 30669468
(Publication Type: Journal Article)
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Chemical References |
- Ceramides
- Enzyme Inhibitors
- Imino Pyranoses
- Imino Sugars
- Piperidines
- Pyrrolidines
- isofagomine
- piperidine
- Glucosylceramidase
- pyrrolidine
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Topics |
- Animals
- Cells, Cultured
- Ceramides
(chemistry)
- Enzyme Inhibitors
(chemistry)
- Fibroblasts
(drug effects)
- Glucosylceramidase
(antagonists & inhibitors, metabolism)
- Humans
- Hydrolysis
- Imino Pyranoses
(chemistry)
- Imino Sugars
(chemistry)
- Isomerism
- Lysosomes
- Melanoma, Experimental
- Mice
- Molecular Docking Simulation
- Molecular Structure
- Piperidines
(chemistry)
- Protein Binding
- Pyrrolidines
(chemistry)
- Structure-Activity Relationship
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