Novel Double-Modified Colchicine Derivatives Bearing 1,2,3-Triazole: Design, Synthesis, and Biological Activity Evaluation

[Image: see text] A series of 1,4-disubstituted 1,2,3-triazoles having 10-demethoxy-10-N-methylaminocolchicine core were designed and synthesized via the Cu(I)-catalyzed “click” reaction and screened for their in vitro cytotoxicity against four cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and one noncancerous cell line (BALB/3T3). Indexes of resistance (RI) and selectivity (SI) were also determined to assess the potential of the analogues to break drug resistance of the LoVo/DX cells and to verify their selectivity toward killing cancer cells over normal cells. The compounds with an ester or amide moiety in the fourth position of 1,2,3-triazole of 10-N-methylaminocolchicine turned out to have the greatest therapeutic potential (low IC(50) values and favorable SI values), much better than that of unmodified colchicine or doxorubicin and cisplatin. Thus, they make a valuable clue for the further search for a drug having a colchicine scaffold.