Novel Cyanoacrylamides Incorporating Sulfamethoxazole as Potential Anticancer Agents: DNA Interaction, Apoptotic Induction, and S-Phase Cell Cycle Arrest in Colon Cancer Cells

In the current study, five novel cyanoacrylamides incorporating sulfamethoxazole (<b>5-9</b>) were designed and synthesized as potential candidates for anticancer therapy. The antitumor potential of the synthesized compounds was screened against HCT116, MDA-MB-231, and A549 human tumor cells. Compound <b>9</b>, incorporating the 4-(piperidin-1-yl)-phenyl moiety, was more effective than 5-fluorouracil against the three cell lines. The shape of colon cancer cells was examined by scanning electron microscope (SEM). Compound <b>9</b> could effectively induce HCT116 apoptosis through the remarkable upregulation of Bax and caspase-3 and the downregulation of Bcl2 and survivin. It can also inhibit HCT116 cell cycle progression at the S phase and cell migration, as it significantly downregulates cyclin A1 and upregulates CDH1, respectively. According to UV-vis and EB-displacement measurements, compound <b>9</b> could interact with CT-DNA in a mild intercalative way. DNA fragmentation propensities of compound <b>9</b> were examined on pBR322 plasmid DNA using gel electrophoresis, revealing that compound <b>9</b> exhibited remarkable photofragmentation activity. Moreover, the molecular docking supported that compound <b>9</b> had good binding affinities toward the active sites of key proteins implicated in carcinogenesis and metastasis. In conclusion, compound <b>9</b> is presented as a remarkable molecule for the development of novel anticancer drugs.