title: Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents.
abstract: Reaction of 10-deacetylbaccatin III (III) and its 7-TES derivative (IV) with DAST under various conditions resulted in the formation of an array of new fluorinated and non-fluorinated 13-keto taxoid compounds (2a–4a) through a vinylogous pinacol–pinacolone rearrangement. Further fluorination of some of these products (2a, 3a) with NFSi or Selectfluor gave additional derivatives. Sodium borohydride reduction of the 13-keto group of these products (2a, 2b, 3a, 3b, 4a, 8, 9, 11–14) led to a series of 9α-hydroxy taxoid derivatives, which were esterified using the docetaxel side chain employing the corresponding protected β-lactam, followed by deprotection to furnish a library of docetaxel analogs and related compounds. A selected number of synthesized compounds (7, 10, 19a, 19b, 21a, 21b, 23, 27, 29, 34–36) were submitted to the National Cancer Institute (NCI) 60 cell line screening program and tested for cytotoxic properties. Taxoids 19a, 19b, 21a, 21b, 23, 27, 29, 34 and 35 were found to exhibit significant anticancer activity against various cancerous cell lines with 23, 27, and 29 being the most potent compounds, demonstrating GI50 values of ≤5 nM in several assays.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
authors.forename: Kyriacos C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Roman A
authors.initials: RA
authors.lastname: Valiulin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020946:Taxus / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; C042213:10-deacetylbaccatine III; D017239:Paclitaxel