Novel cyanochalcones as potential anticancer agents: apoptosis, cell cycle arrest, DNA binding, and molecular docking studies

In the light of anticancer drug discovery and development, a new series of cyanochalcones incorporating indole moiety (5a-g) were efficiently synthesized and characterized by different spectral analysis. MTT assay was used to evaluate the antiproliferative activity of the synthesized compounds towards different cancer cells (Hela, MDA-MB-231, A375, and A549) in parallel with normal cells (HSF). Trimethoxy and diethoxy-containing derivatives (5d and 5e) displayed the most selective cytotoxic activities against cervical Hela cells with IC50 values of 8.29 and 11.82 µM, respectively, with great safety pattern toward normal HSF cells (Selectivity index: 21.3 and 13.9, respectively). Therefore, 5d and 5e were chosen to study their effects on apoptosis, cell cycle arrest, and migration of Hela cells using flow cytometric analysis and wound healing assay. They induced apoptosis and cell cycle arrest at the S phase and impaired migration of HeLa cells. Regarding their effects on the expression profile of crucial genes related to the potential anticancer activities, 5d and 5e remarkably upregulated caspase 3 and Beclin1 and downregulated cyclin A1, CDK2, CDH2, MMP9, and HIF1A using qRT-PCR and ELISA techniques. UV–Vis spectral measurement demonstrated the ability of 5d and 5e to bind CT-DNA efficiently with Kb values of 3.7 × 105 and 1 × 105 M−1, respectively. Moreover, in silico molecular docking was performed to assess the binding affinities of the compounds toward the active sites of Bcl2, CDK2, and DNA. Therefore, cyanochalcones 5d and 5e might be promising anticancer agents and could offer a scientific basis for intensive research into cancer chemotherapy. Communicated by Ramaswamy H. Sarma A novel series of cyanochalcones incorporating indole moiety (5a–g) were designed and synthesized.Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF).5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells.5d and 5e demonstrated good DNA binding affinities.Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA. A novel series of cyanochalcones incorporating indole moiety (5a–g) were designed and synthesized. Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF). 5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells. 5d and 5e demonstrated good DNA binding affinities. Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA.</p