Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives for anticancer activity

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 antitumour agents. Experimental Approach 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. 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 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. 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.