Synthesis and biological evaluation of phenstatin metabolites
作者： Alina Ghinet , Benoît Rigo , Jean-Pierre Hénichart , Delphine Le Broc-Ryckewaert , Jean Pommery
DOI: 10.1016/J.BMC.2011.08.047
关键词: Tubulin 、 Active metabolite 、 Microtubule 、 In vitro 、 Chemistry 、 Cell culture 、 Biochemistry 、 Metabolite 、 Microsome 、 Structure–activity relationship
摘要: Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed formation nine main metabolites. The structures eight these metabolites have been now confirmed by synthesis their biological properties reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, simple multigram scale preparation phenstatin. Synthesized related compounds were evaluated for antiproliferative activity in NCI-60 cancer cell line panel, effect microtubule assembly. Metabolite 23 (2'-methoxyphenstatin) exhibited most potent vitro cytotoxic activity: inhibition growth K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, HS 578T lines GI(50) values <10nM. It also showed more significant tubulin polymerization inhibitory than parent (3) (IC(50)=3.2 μM vs 15.0 μM) induced G2/M arrest murine leukemia DA1-3b cells. identification this active metabolite led to design analogs cytotoxicity
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