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

ABSTRACT: 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 GI50 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 GI50 range of 0.011-0.19 ?M. In further studies, active compounds 6b-e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92-1.0 ?M and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75-99% (at 5 ?M), comparable with or more potent than combretastatin A-4 (IC50 0.96 ?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.

SUBMITTER: Wang XF 

PROVIDER: S-EPMC3770484 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature