title: 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 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.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Pharmacy Department, Urumqi General Hospital, Lanzhou Military Region, Urumqi 830000, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Sheng-Biao
authors.initials: SB
authors.lastname: Wang
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007624:KB Cells; D008958:Models, Molecular; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011804:Quinolines; D014404:Tubulin; C542964:1,2,3,4-tetrahydroquinoline; D003078:Colchicine
keywords: 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