RESUMEN
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.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Cromonas , Ensayos de Selección de Medicamentos Antitumorales , Tiazolidinedionas , Humanos , Apoptosis/efectos de los fármacos , Cromonas/farmacología , Cromonas/química , Cromonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tiazolidinedionas/farmacología , Tiazolidinedionas/química , Tiazolidinedionas/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Células HEK293 , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Línea Celular TumoralRESUMEN
An efficient Rh(III)-catalysed C-H functionalization, tandem annulation of cis-stilbene acids using 2-diazo-1,3-diketones was devised. This protocol solely afforded 6,7-dihydrobenzofuran-4(5H)-ones using alicyclic diazocarbonyls via decarbonylation and α-pyrones with aliphatic diazo compounds. The chameleonic nature of cis-stilbene acid was observed with various diazo compounds by altering the additives. This synthetic method furnished good atom-economy and wide functional group tolerance, and also explained the use of carboxylic acids as a directing group. In addition, a mechanistic investigation of the catalysed reaction using ESI-MS, and the fluorescence properties of α-pyrones were well explored.