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 μM). 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 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.