title: Synthesis and SAR studies of novel 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives for anticancer activity.
abstract: OBJECTIVE
  4-Phenylquinolin-2(1H)-one (4-PQ) derivatives can induce cancer cell apoptosis. Additional new 4-PQ analogs were investigated as more effective, less toxic antitumour agents.
  
  
  METHODS
  Forty-five 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives were synthesized. Antiproliferative activities were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide assay and structure-activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute-60 human cancer cell line panel. Hoechst 33258 and Annexin V-FITC/PI staining assays were used to detect apoptosis, while inhibition of microtubule polymerization was assayed by fluorescence microscopy. Effects on the cell cycle were assessed by flow cytometry and on apoptosis-related proteins (active caspase-3, -8 and -9, procaspase-3, -8, -9, PARP, Bid, Bcl-xL and Bcl-2) by Western blotting.
  
  
  RESULTS
  Nine 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives (7e, 8e, 9b, 9c, 9e, 10c, 10e, 11c and 11e) displayed high potency against HL-60, Hep3B, H460, and COLO 205 cancer cells (IC₅₀ < 1 μM) without affecting Detroit 551 normal human cells (IC₅₀ > 50 μM). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G2/M arrest, polyploidy and apoptosis via the intrinsic and extrinsic signalling pathways. Activation of JNK could play a role in TRAIL-induced COLO 205 apoptosis.
  
  
  CONCLUSIONS
  New quinolone derivatives were identified as potential pro-apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan; School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yi-Fong
authors.initials: YF
authors.lastname: Chen
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lin
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Chen-Fang
authors.initials: CF
authors.lastname: Wei
authors.forename: Ting-Chen
authors.initials: TC
authors.lastname: Shen
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chou
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones