Development of chromone-thiazolidine-2,4-dione Knoevenagel conjugates as apoptosis inducing agents

Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro Cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC₅₀ concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC₅₀ of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 Family) with comparable binding affinities.

Anticancer; Apoptosis; Bcl-2; Chromone; Knoevenagel condensation; Thiazolidinedione.