title: Synthesis and biological evaluation of phenstatin metabolites.
abstract: Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed the formation of nine main metabolites. The structures of eight of these metabolites have been now confirmed by synthesis and their biological properties have been reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, a simple multigram scale preparation of phenstatin. Synthesized metabolites and related compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell line panel, and for their effect on microtubule assembly. Metabolite 23 (2'-methoxyphenstatin) exhibited the most potent in vitro cytotoxic activity: inhibition of the growth of K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, and HS 578T cell lines with GI(50) values <10nM. It also showed more significant tubulin polymerization inhibitory activity than parent phenstatin (3) (IC(50)=3.2 μM vs 15.0 μM) and induced G2/M arrest in murine leukemia DA1-3b cells. The identification of this active metabolite led to the design and synthesis of analogs with potent in vitro cytotoxicity and inhibition of microtubule assembly.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France.
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
authors.forename: Benoît
authors.initials: B
authors.lastname: Rigo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hénichart
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Broc-Ryckewaert
authors.forename: Jean
authors.initials: J
authors.lastname: Pommery
authors.forename: Nicole
authors.initials: N
authors.lastname: Pommery
authors.forename: Xavier
authors.initials: X
authors.lastname: Thuru
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010755:Organophosphates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D010755:Organophosphates; D014404:Tubulin; D050257:Tubulin Modulators; C112107:phenstatin phosphate