Flexible and enantioselective access to jaspine B and biologically active chain-modified analogues thereof.

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Salma, Yahya | Ballereau, Stéphanie | Maaliki, Carine | Ladeira, Sonia | Andrieu-Abadie, Nathalie | Génisson, Yves

Edité par CCSD ; Royal Society of Chemistry -

International audience. Whereas the all-cis tetrahydrofuran framework of the cytotoxic anhydrophytosphingosine jaspine B is considered as a relevant pharmacophore, little is known about the influence of the aliphatic chain of this amphiphilic molecule on its activity. We developed a synthetic strategy allowing flexible introduction of various lipophilic fragments in the jaspine's skeleton. The route was validated with two distinct approaches to jaspine B. Five chain-modified analogues were also prepared. Biological evaluation of these derivatives demonstrated a good correlation between their cytotoxicity and their capacity to inhibit conversion of ceramide into sphingomyelin in melanoma cells. A series of potent and selective inhibitors of sphingomyelin production was thus identified. Furthermore, the good overall potency of an ω-aminated analogue allowed us to dissociate of the pharmacological action of jaspine B from its amphiphilic nature.

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