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Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.

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.

Umbelliprenin has recently been shown to have great potential as a skin whitening agent. Wishing to investigate the same effect in plant species known to biosynthesize this coumarin, three plants belonging to the Apiaceae family, namely Anethum graveolens L. (dill), Pimpinella anisum L. (anise), and Ferulago campestris (Besser) Grecescu (field ferula) were screened by HPLC analysis for their respective content of umbelliprenin in extracts obtained with different solvent mixtures and by maceration and ultrasound-assisted processes. EtOH was shown to be the best solvent, providing umbelliprenin yields ranging from 1.7% to 14.4% (with respect to the total amount of extract obtained). Extracts with the highest content of this farnesyloxycoumarin were then assayed as modulators of melanogenesis in cultured murine Melan A cells employing the same umbelliprenin obtained by chemical synthesis as the reference. A parallelism between the content of the coumarin and the recorded depigmenting effect (60% for the EtOH extract of F. campestris as the best value) was revealed for all plants extracts when applied at a dose of 100 μg/mL. Our results demonstrate that the same potential of umbelliprenin can be ascribed also to umbelliprenin-enriched plant extracts which reinforces enforce the widespread use of phyto-preparations for cosmetic purposes (e.g., A. graveolens).