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 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.

BJGUNGDUBFAZJF-UHFFFAOYSA-N; CKJVPMVADPIXNN-UHFFFAOYSA-N; Colchicine binding site; Cytotoxicity; FDQUVMAKHZXEJX-UHFFFAOYSA-N; FDYCTHWQCNDDJL-UHFFFAOYSA-N; FTMZJCYHPDAWMW-UHFFFAOYSA-N; GZMJPFYDEOCCRA-UHFFFAOYSA-N; HHKPUUIFQNECJS-UHFFFAOYSA-N; HUKWJNYCEZDAFN-UHFFFAOYSA-N; HUZJMKBTGUFMFQ-UHFFFAOYSA-N; HYOBVXAUEHOWFL-UHFFFAOYSA-N; IGSCZPCABVOJSO-UHFFFAOYSA-N; JOQRIEZWVNWGML-UHFFFAOYSA-N; JRQKACCJXWRRCO-UHFFFAOYSA-N; JZGLPKGGBIDFME-UHFFFAOYSA-N; KFOXZZAYGWYTRQ-UHFFFAOYSA-N; N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines; NVIYNSOOPAAJBH-UHFFFAOYSA-N; OCEFQUWNZIDEES-UHFFFAOYSA-N; ORBAISZLWSRHJS-UHFFFAOYSA-N; PJOIMWRREFTKKZ-UHFFFAOYSA-N; QZGXGAIVITUVSU-UHFFFAOYSA-N; SDVCOWGIPMODEC-UHFFFAOYSA-N; SXLFBMRIJWONFS-UHFFFAOYSA-N; Tubulin polymerization inhibitors; UOSMAUJRTJCCEL-UHFFFAOYSA-N; VQIAEEFDUGUMGV-UHFFFAOYSA-N; YVMCASKEHBSJQW-UHFFFAOYSA-N.