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

Abstract

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.

Synthesis, Characterization and In Vitro Evaluation of Novel 5-Ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones as Possible Anticancer Agents

“…The selectivity index (SI) calculated by dividing the full panel MG _ MID (full-panel mean-graph midpoint) (μM) of the compounds 2h and 2i by their individual subpanel MG_MID of a cell line (μM) was considered as a measure of compounds’ selectivity. Ratios between 3 and 6 mean moderate selectivity, ratios greater than 6 indicate high selectivity toward the corresponding cell line, while compounds not meeting either of these criteria are rated nonselective [ 38 , 55 ].…”

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

“…[214] Modification of the basic flavone pharmacophore by translation of the 2-phenyl ring, such as in the 4-phenylquinolin-2(1H)-ones, leads to aza-podophyllotoxin analogues with much less potent cytotoxic activity, [217] but elongation of the linker to the quinoline has resulted again in nanomolar cytotoxic compounds. [218] Structurally related acridones with pendant phenethyl substituent have also been shown to be potent TPI, an activity which is not accompanied by potent cytotoxicity against cancer cells in vitro. [219]…”

Aryl and heteroaryl azo dyes derived from 6, 8‐dichloro‐4‐hydroxyquinolin‐2 (1H)‐one: synthesis, characterisation, solvatochromism and spectroscopic properties

“…Quinoline‐2‐one is an important structural moiety in a variety of natural and synthetic products that possess significant pharmaceutical properties . There are many papers that have reported the synthesis and properties of quinoline‐2‐ones and a large number of their derivatives . In addition, 4‐hydroxyquinolin‐2(1 H )‐one and its derivatives have been found to serve as suitable intermediates in the synthesis of some azo disperse dyes .…”

“…10,11 There are many papers that have reported the synthesis and properties of quinoline-2-ones and a large number of their derivatives. 12,13 In addition, 4-hydroxyquinolin-2(1H)-one and its derivatives have been found to serve as suitable intermediates in the synthesis of some azo disperse dyes. 14 CI Pigment Yellow 7, CI Mordant Red 30 and 3-arylazo-5, 6, 7, 8-tetrafluoro-2, 4-quinolinediol can be considered to be early examples of 4-hydroxyquinolin-2(1H)-one-based azo dyes (Scheme 1).…”