N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: A novel class of antitumor agents targeting the colchicine site on tubulin

Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI(50) values ranging from 1.5 to 1.7 nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogs 5f, 6b, 6c, and 6e were also quite potent, with a GI(50) range of 0.011-0.19 mu M. In further studies, active compounds 6b e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92 -1.0 mu M and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75-99% (at 5 mu M), comparable with or more potent than combretastatin A-4 (IC50 0.96 mu M). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3-6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in vitro metabolic stability, were also performed. (C) 2013 Elsevier Masson SAS. All rights reserved.