Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

A series of novel N,2-diphenyl-6-(aryl/heteroaryl)quinoline-4-carboxamide derivatives were designed and synthesized using the Suzuki coupling reaction and evaluated them for their anticancer activity. These compounds were screened for anti-colon cancer activity through in-silico studies by molecular docking and molecular dynamics studies. Furthermore, the density functional theory was used to determine the molecule's electrical properties. The molecular electrostatic potential map is used to evaluate the charge distribution on the molecule surface. Unveiling that the compound 7a (binding energy of −10.2 kcal/mol) has good inhibition activity compared to other synthesized compounds (7b-7j) as well as the standard drug Gefitinib. The stability of the compound 7a with the 1OKY protein was confirmed through molecular dynamics simulation studies, indicating potential anti-colon cancer activity against phosphoinositide dependent protein kinase-1 (PDK1). The in-silico ADMET pharmacokinetic properties indicate adherence to Lipinski's rule of five for favorable safety profiles and the compound falls within the optimal range for physicochemical and pharmacokinetic properties, which is comparable to that of the standard medication drug Gefitinib. The synthesized library of compounds was further evaluated for their in-vitro anticancer potency against colon, pancreatic and breast cancer cells. The results demonstrated that the compounds effectively suppressed the proliferative potential of the screened cells in a concentration-dependent manner, as revealed by MTT assay. The anticancer potential of these molecules was further evaluated by acridine orange/PI, and Hoechst/PI which demonstrates the potential of molecules to induce apoptosis in cancer cells. Further investigations and optimization of these derivatives could lead to the development of effective anticancer strategies.