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Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1 H )‐one derivatives for anticancer activity
Author(s) -
Chen YiFong,
Lin YiChien,
MorrisNatschke Susan L,
Wei ChenFang,
Shen TingChen,
Lin HuiYi,
Hsu MeiHua,
Chou LiChen,
Zhao Yu,
Kuo ShengChu,
Lee KuoHsiung,
Huang LiJiau
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12992
Subject(s) - apoptosis , flow cytometry , chemistry , cell cycle , cell culture , potency , cell cycle checkpoint , microbiology and biotechnology , cancer cell , stereochemistry , cancer , biochemistry , biology , in vitro , genetics
Background and Purpose 4‐ P henylquinolin‐2(1 H )‐one (4‐ PQ ) derivatives can induce cancer cell apoptosis. Additional new 4‐ PQ analogs were investigated as more effective, less toxic antitumour agents. Experimental Approach Forty‐five 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1 H )‐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 N ational C ancer I nstitute‐60 human cancer cell line panel. Hoechst 33258 and A nnexin 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 , B id, B cl‐x L and B cl‐2) by Western blotting. Key Results Nine 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1 H )‐one derivatives ( 7e , 8e , 9b , 9c , 9e , 10c , 10e , 11c and 11e ) displayed high potency against HL ‐60, H ep3 B , H 460, and COLO 205 cancer cells ( IC 50 < 1 μ M ) without affecting D etroit 551 normal human cells ( IC 50 > 50 μ M ). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G 2/ 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. Conclusion and Implications New quinolone derivatives were identified as potential pro‐apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.