Flexible and enantioselective access to jaspine B and biologically active chain-modified analogues thereof.
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 omega-aminated analogue allowed us to dissociate of the pharmacological action of jaspine B from its amphiphilic nature.
Salma
Yahya
Y
LSPCMIB, UMR5068, CNRS-Université Paul Sabatier, Toulouse, France.
Ballereau
Stéphanie
S
Maaliki
Carine
C
Ladeira
Sonia
S
Andrieu-Abadie
Nathalie
N
Génisson
Yves
Y
D000114:Acetylene / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020128:Inhibitory Concentration 50; D051379:Mice; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013379:Substrate Specificity; D014753:Vinyl Compounds / Q000737:chemistry
D000447:Aldehydes; D000970:Antineoplastic Agents; D014753:Vinyl Compounds; C468594:pachastrissamine; D013110:Sphingosine; D000114:Acetylene