Synthesis, computational studies, and biological evaluation of novel cyanoacrylamides as potential anticancer agents

A novel series of cyanoacrylamides based on thiazole was synthesized and characterized by different physicochemical and multispectral investigations. The new compounds have been assessed for their cytotoxic potential against several human cancer cell lines (HCT-116, MCF-7, HEp-2, and WI-38). Compound 5g, incorporating 4-(piperidin-1-yl)phenyl moiety, was selected as it emerged to achieve the potent cytotoxic effect against HCT-116 and MCF-7 cell lines, with IC₅₀ values of 32 and 49 µM, respectively. In addition, the selectivity index was calculated to be > 3.1 against the HCT-116 cell line, where it exhibits a low cytotoxic effect against the WI-38 cell line. Compound 5g also has the capability to induce both early and late apoptosis of HCT-116 cells. Moreover, flow cytometric analysis of HCT-116 cells treated with compound 5g showed a pronounced increase in cells in the S and G2/M phases with a consequent reduction of cells in the G₀/G1 phase, indicating that compound 5g induces cell cycle arrest and apoptosis. In addition, the results were confirmed by increased caspase-3 activity, downregulation of Bcl-2, CDK1, and CDK2 expression, and upregulation of Bax expression, as evidenced by qRT-PCR and ELISA analyses. Additionally, 5g exhibited a favorable DNA binding affinity as determined through UV-Vis measurements with a K_b value of 1.39 × 10⁴ M^-1. The drug-like features of 5g were evaluated, and its ADMET properties were predicted. Moreover, a molecular docking study of 5g was performed with different proteins, Bcl2, CDK1, and CDK2, which generates a docking score value range from -4.78 to -7.06 kcal mol^-1.