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

• Published in: Bioorganic & medicinal chemistry letters 2024-09, Vol.109, p.129853, Article 129853
• Main Authors: Galla, Mary Sravani, Kale, Nandini B., Sharma, Anamika, Hajare, Aditya, Godugu, Chandraiah, Shankaraiah, Nagula
• Format: Article
• Language: English
• Subjects: Anticancer; Apoptosis; Bcl-2; Chromone; Knoevenagel condensation; Thiazolidinedione
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129853

[Display omitted] •Novel chromone-TZD hybrids were designed, synthesized as Bcl-2 inhibitors.•Compound 8l was found to be active against A549 cell line with an IC50 of 6.1 µM.•ROS, staining assays, cell cycle analysis was performed, evidencing the apoptosis.•Reduced expression of Bcl-2 was observed with 79.1 % at 9 µM for compound 8l.•In-silico docking study also supports the apoptotic nature of designed molecules. 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.