Document Detail

Synthesis and SAR studies of novel 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives for anticancer activity.
MedLine Citation:
PMID:  25363404     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: 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 antitumor agents.
EXPERIMENTAL APPROACH: Forty-five 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives were synthesized. Anti-proliferative activities were evaluated using an MTT assay, and structure-activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute (NCI)-60 human cancer cell line panel. Hoechst 33258 and Annexin V-FITC/ PI staining assays showed that 11e induced apoptosis of COLO 205 cells, while fluorescence microscopy experiments revealed inhibition of microtubule polymerization. Compound 11e-treatment influenced expression of cell cycle- and apoptosis-related proteins in COLO 205 cells, causing G2/M arrest and multi-nucleation. Compound 11e also increased levels of active caspase-3, -8, and -9 forms, but reduced procaspase-3, -8, -9, PARP, Bid, Bcl-xL, and Bcl-2.
KEY 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 11e exerts anticancer effects by disrupting microtubule assembly and inducing G2/M arrest, polyploidy, and apoptosis via intrinsic and extrinsic signaling pathways. Activation of JNK might play a role in TRAIL-induced COLO 205 apoptosis.
CONCLUSION AND IMPLICATIONS: New quinolone derivatives were identified as potential pro-apoptotic agents. Compound 11e should be used as a promising lead compound for future antitumor agent development.
Yi-Fong Chen; Yi-Chien Lin; Susan L Morris-Natschke; Chen-Fang Wei; Ting-Chen Shen; Hui-Yi Lin; Mei-Hua Hsu; Li-Chen Chou; Yu Zhao; Sheng-Chu Kuo; Kuo-Hsiung Lee; Li-Jiau Huang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-3
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-3     Completed Date:  -     Revised Date:  2014-11-5    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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This article is protected by copyright. All rights reserved.
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