title: Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability.
abstract: 2-Methoxyestradiol is a cytotoxic human metabolite of estradiol with the ability to bind to the colchicine site of tubulin and inhibit its polymerization, and its 2-ethoxy analogue is even more potent. On the basis of a hypothetical relationship between the structures of colchicine and 2-methoxyestradiol, a B-ring-expanded 2-ethoxyestradiol analogue was synthesized in which the B-ring of the steroid is replaced by the B-ring of colchicine. The synthesis relied on the B-ring expansion of available 6-keto estradiol derivatives as opposed to a total synthesis of the homologated steroid framework. The relative configurations of the acetamido substituents in both epimers of the final product were determined by NOESY NMR and confirmed by X-ray crystallography. The epimer having the 6alpha-acetamido substituent was more active as an inhibitor of tubulin polymerization, and it was also more cytotoxic than the 6beta-epimer. These results are consistent with the proposed structural resemblance of 2-methoxyestradiol and colchicine. Several of the synthetic intermediates proved to be potent inhibitors of tubulin polymerization. On the other hand, a 3,17beta-diacetylated, B-ring-expanded analogue of 2-ethoxyestradiol having a ketone at C-6 resembled paclitaxel (Taxol) in its ability to enhance tubulin polymerization and stabilize microtubules. The corresponding 3-acetate and the 17beta-acetate were both synthesized, and it was determined that the 17beta-acetate, but not the 3-acetate, conferred on the steroid derivative its paclitaxel-like activity.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, and Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: A K
authors.initials: AK
authors.lastname: Mohanakrishnan
authors.forename: P E
authors.initials: PE
authors.lastname: Fanwick
authors.forename: P
authors.initials: P
authors.lastname: Nampoothiri
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: M
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008870:Microtubules / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D004958:Estradiol; D017239:Paclitaxel