title: Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth.
abstract: A new series of estradiol analogs was synthesized in an attempt to improve on the anticancer activity of 2-methoxyestradiol, a naturally occurring mammalian tubulin polymerization inhibitor. The compounds were evaluated as inhibitors of tubulin polymerization and the binding of [3H]colchicine to tubulin, as well as for in vitro cytotoxicity in human cancer cell cultures. Overall, the most potent of the new compounds were 2-(2',2',2'-trifluoroethoxy)-6-oximinoestradiol, 2-ethoxy-6-oximinoestradiol, and 2-ethoxy-6-methoximinoestradiol. These agents lacked significant affinity for the estrogen receptor. The cytotoxicities of the compounds correlated in general with their abilities to inhibit tubulin polymerization, thus supporting inhibition of tubulin polymerization as the primary mechanism causing inhibition of cell growth.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cushman
authors.forename: H M
authors.initials: HM
authors.lastname: He
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: R K
authors.initials: RK
authors.lastname: Varma
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: C M
authors.initials: CM
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Ram
authors.forename: Y P
authors.initials: YP
authors.lastname: Sachdeva
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001704:Biopolymers; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D001704:Biopolymers; D011960:Receptors, Estrogen; D014404:Tubulin; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol