title: Synthesis and evaluation of water-soluble non-prodrug analogs of docetaxel bearing sec-aminoethyl group at the C-10 position.
abstract: To develop non-prodrugs of taxoids with satisfactory stability in vivo, high water-solubility, and potent antitumor activity, we prepared several 10-O-sec-aminoethyl docetaxel analogs (3) and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines, microtubule disassembly-inhibitory activity, and water-solubility. These analogs were synthesized from the 10-O-allyl baccatin derivatives (5a-c) using the beta-lactam synthon method. Among these analogs, the 10-O-(2-morpholinoethyl) (18, 21) and 10-O-(2-thiomorpholinoethyl) (19, 24) analogs exhibited cytotoxicity comparable or superior to that of docetaxel (2). In addition, the methanesulfonic acid salt (18a) had a high water-solubility.
authors.affiliation: New Product Research Laboratories IV, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uoto
authors.forename: H
authors.initials: H
authors.lastname: Takenoshita
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: S
authors.initials: S
authors.lastname: Ando
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* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D012995:Solubility; D013552:Swine; D043823:Taxoids; D014404:Tubulin / Q000737:chemistry / Q000302:isolation & purification
chemical_list: C112901:10-O-sec-aminoethyl docetaxel; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D017239:Paclitaxel