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

• New N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines inhibited tubulin polymerization.
• Compound 6d significantly inhibited colchicine binding (99%, 5 μM; 95%, 1 μM).
• Compound 6d was more potent than anticancer drug paclitaxel (GI50 1.5–1.7 nM).
• A fused aromatic ring, such as quinoline and quinazoline, improved molecular potency.
• A feasible torsional angle between the two aryl rings is important for high potency.

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

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