Design and synthesis of new 1,2,3-triazole derivatives as VEGFR-2/telomerase downregulatory candidates endowed with apoptotic potential for cancer treatment.

In this current work, we dedicated efforts to designing and synthesizing new 1,2,3-triazole-analogues (5a-d), (6a-d), and (7a-c) to act as dual VEGFR-2 and telomerase inhibitors with promising apoptotic potential. The synthesized analogues were examined against eleven diverse types of cancer cells and two normal cells to assess their ability to inhibit cell growth (GI%). Obviously, compound 7b showed the best average GI% (75.69 %) surpassing the average GI% of Dox (65.79 %). Compound 5d showed the lowest IC50 values (25.86 and 51.91 µM) against HNO-97 and FaDu cancer cells, respectively. Besides, compound 5a exhibited the lowest IC50 value (15.46 µM) against HCT116, whereas compound 6b revealed the lowest IC50 value (31.14 µM) against HuH7. Besides, candidates 5a, 5b, 5d, and 7a showed prominent inhibitory results towards VEGFR-2 protein with decreasing its expression by 0.33, 0.42, 0.38 and 0.26-fold change, respectively. However, compounds 5a, 5b, 5d, and 7a showed promising inhibitory results towards telomerase protein and decreased its expression by 0.60, 0.50, 0.52, and 0.44-fold change, respectively. Additionally, it was clear that compound 5a was able to upregulate the expression of Caspases 3, 8, and 9 proteins by 2.19, 1.83, and 1.62-fold change, respectively. Besides, 5a was able to downregulate the expression of CDK-2, CDK-4, and CDK-6 proteins by 0.50, 0.43, and 0.13-fold change, respectively. Obviously, compound 5a halted the cell cycle at the G1, S, and G2-M phases in HCT116 cells. Subsequently, the synthesized 1,2,3-triazole analogues can be treated as lead VEGFR-2 and telomerase inhibitors with potential apoptotic activity for future optimization and cancer treatment.