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

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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 IC 50 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 IC 50 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.

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