Multi-Target Rational Design and Synthesis of Some 2-Quinolinone Antitumor Candidates Downregulating the Expression...

The literature represented that the 2-quinolone moiety is present in diverse potent EGFR, VEGFR-2, and telomerase cellular downregulators. Accordingly, it was incorporated in new scaffolds (2, 3, 5, and 8-12), keeping in mind its attachment to the requested pharmacophores of more than one target receptor to produce novel multi-target ligands. First, the growth inhibition % (GI%) of all candidates was recorded in seven diverse human cancer cell lines. Second, the IC₅₀ values of compounds (5, 6, and 12) were determined against six cancer cell lines. Interestingly, analogue (6) displayed the highest cytotoxicity, particularly against CaCo2, with an IC₅₀ value of 21.99 µM. Then, the EGFR, VEGFR-2, and telomerase inhibitory potentials of compounds (5, 6, and 12) were recorded. Notably, compound 6 showed the highest EGFR, VEGFR-2, and telomerase inhibitory potentials with 0.34, 0.31, and 0.54-fold changes, respectively. Additionally, the apoptotic potency of analogue (6) was evaluated by measuring the expression of caspases 3, 8, and 9 (proapoptotic markers), besides CDK 2, 4, and 6 (antiapoptotic markers) proteins. To sum up, compound 6 showed remarkable upregulation of the caspases 3, 8, and 9, while it showed detrimental results against the CDK 2, 4, and 6 proteins. This further emphasizes the potent apoptotic potential of compound 6 in CaCo2 cancer cells. Moreover, compound 6's impact on cell cycle progression in CaCo2 showed a notable increase in cell cycle arrest in the G0 and G1 phases, equivalent to 28.72% and 68.20%, respectively, relative to control cells with 25.77% and 60.49%, respectively. Furthermore, the superior antitumor analogue (6) was tested by in silico molecular docking and dynamic simulations (for 200 ns) against EGFR, VEGFR-2, and telomerase targets to investigate its affinity and interactions. A structure-activity relationship (SAR) was performed to determine the anticancer potential of the tested candidates through modifications to the 2-oxoquinoline-3-carbaldehyde scaffold.