title: A steroid derivative with paclitaxel-like effects on tubulin polymerization.
abstract: The endogenous estrogen metabolite 2-methoxyestradiol has modest antimitotic activity that may result from a weak interaction at the colchicine binding site of tubulin, but it nevertheless has in vivo antitumor activity. Synthetic efforts to improve activity led to compounds that increased inhibitory effects on cell growth, tubulin polymerization, and binding of colchicine to tubulin. This earlier work was directed at modifications in the steroid A ring, which is probably analogous to the colchicine tropolonic C ring. One of the most active analogs prepared was 2-ethoxyestradiol (2EE). We report here that different modifications in the steroid B ring of 2EE yield compounds with two apparently distinct modes of action. Simple expansion of the B ring to seven members resulted in a compound comparable to 2EE in its ability to inhibit tubulin polymerization and colchicine binding to tubulin. Acetylation of the hydroxyl groups in this analog and in 2EE essentially abolished these inhibitory properties. The introduction of a ketone functionality at C6, together with acetylation of the hydroxyls at positions 3 and 17, produced a compound with activity similar to that of paclitaxel, in that the agent enhanced tubulin polymerization into polymers that were partially stable at 0 degrees C. The acetyl group at C17, but not that at C3, was essential for this paclitaxel-like activity.
authors.affiliation: Laboratory of Drug Discovery Research, Division of Cancer Treatment, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Verdier-Pinard
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: A K
authors.initials: AK
authors.lastname: Mohanakrishnan
authors.forename: M
authors.initials: M
authors.lastname: Cushman
authors.forename: E
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001704:Biopolymers; D002417:Cattle; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects* / Q000648:ultrastructure; D050257:Tubulin Modulators
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001704:Biopolymers; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D050257:Tubulin Modulators; D018698:Glutamic Acid; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017239:Paclitaxel