Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Kozaka, Takashi¹  Nakagawa-Goto, Kyoko¹  Shi, Qian¹  Lai, Chin-Yu¹  Hamel, Ernest²  Bastow, Kenneth F.³  Brossi, Arnold¹  Lee, Kuo-Hsiung¹ 

[1] Univ N Carolina, Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA

[2] NIH, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA

[3] Univ N Carolina, Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA

关键词: N-Alkylthiocolchinoids;    Antitumor agents;    Tubulin polymerization;   

DOI  :  10.1016/j.bmcl.2010.05.081

来源: Elsevier

【 摘 要 】

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 mu M). 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 mu g/mL) cells and the parent KB (0.0200 mu g/mL) cell line. (C) 2010 Elsevier Ltd. All rights reserved.

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