title: In vitro metabolism of phenstatin: potential pharmacological consequences.
abstract: Phenstatin and its derivatives are potential anticancer drug candidates according to their inhibitory properties on tubulin polymerization, cell growth and antivascular activity. However, at the present time, neither pharmacological nor metabolic studies have been conducted in order to strengthen the relevance of phenstatine as a drug discovery candidate. In the present work, the metabolic fate of phenstatin in rat and human microsomal preparations was studied to investigate the stability of this tubulin polymerization inhibitor and any effects of the metabolites on polymerization and on PC3 cancer cell proliferation. The metabolites were separated by high-performance liquid chromatography and, after their synthesis, characterized by simultaneous LC-DAD-UV and LC-ESI-MS analyses. Thus, eight metabolites were identified. The major biotransformation pathways are carbonyl reduction, O-methylation at C-3', O-methylation after aromatic hydroxylation at the position C-2' on phenyl B ring and O-demethylation on A ring. Four of the identified metabolites were as active or more active, than phenstatin in vitro. Moreover, the better stability of phenstatin versus CA-4 and the lack of quinone formation could justify the design of new analogues which could include various substituents on phenyl rings or linker group in order to modulate the metabolism of phenstatin toward even more active metabolites and so up-regulate the pharmacological activity.
authors.affiliation: Laboratoire de Toxicologie; Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Broc-Ryckewaert
authors.forename: Nicole
authors.initials: N
authors.lastname: Pommery
authors.forename: Jean
authors.initials: J
authors.lastname: Pommery
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Wiart
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautret
authors.forename: Benoît
authors.initials: B
authors.lastname: Rigo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hénichart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001577:Benzophenones / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D010755:Organophosphates; D014404:Tubulin; C112107:phenstatin phosphate