title: Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents.
abstract: As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC(50)=0.88-1.1 microM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED(50) values obtained against P-gp over-expressing KBvin (0.0146 microg/mL) cells and the parent KB (0.0200 microg/mL) cell line.
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kozaka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D003078:Colchicine