title: Synthesis and structure-activity relationships of novel 2',2'-difluoro analogues of docetaxel.
abstract: To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2',2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1 and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p) analogues showed activity comparable or superior to that of docetaxel (2).
authors.affiliation: New Product Research Laboratories IV, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uoto
authors.forename: S
authors.initials: S
authors.lastname: Ohsuki
authors.forename: H
authors.initials: H
authors.lastname: Takenoshita
authors.forename: T
authors.initials: T
authors.lastname: Ishiyama
authors.forename: S
authors.initials: S
authors.lastname: Iimura
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: I
authors.initials: I
authors.lastname: Mitsui
authors.forename: H
authors.initials: H
authors.lastname: Terasawa
authors.forename: T
authors.initials: T
authors.lastname: Soga
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004396:Coloring Agents; D018360:Crystallography, X-Ray; D000077143:Docetaxel; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D043823:Taxoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin / Q000737:chemistry / Q000302:isolation & purification; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D043823:Taxoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D000077143:Docetaxel; C022616:thiazolyl blue; D017239:Paclitaxel