Multi-Target Rational Design and Synthesis of Some 2-Quinolinone Antitumor Candidates Downregulating the Expression of EGFR, VEGFR-2, and Telomerase With Apoptotic Potential

Abstract

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.