New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation.

Background: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects.

Purpose: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxaline-based derivatives was designed and synthesized on the basis of the pharmacophoric features of VEGFR-2 inhibitor drugs.

Methods: The new candidates were evaluated against A549 lung cancer cells, HepG-2 hepatoma cells, Caco-2 colon cancer cells, MDA breast cancer cells, and VEGFR-2 kinase. Moreover, cell cycle kinetics and apoptosis rates were studied in HepG-2 cells treated with compound , which was the most promising candidate.

Results: The new derivatives revealed better antitumor results (IC from 6.48 to 38.58 µM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC values ranging from 0.19 to 0.60 µM compared to 0.08 µM for sorafenib. Compound , meanwhile, showed IC values equal to 10.61, 9.52, 12.45, 11.52, and 0.19 µM against the cancer cell lines and VEGFR-2, respectively. Moreover, compound raised the apoptosis rate in HepG-2 cells from 5% to 44% and caused 4, 2.3, and 3-fold increases in BAX/Bcl-2 ratio, caspase-3 level, and P53 expression, respectively, compared to control untreated cells. Finally, the new derivatives displayed the correct binding mode into VEGFR-2 kinase pocket, giving interactions with the essential residues.

Conclusion: This work suggests that compound is a very significant anticancer candidate, and piperazinylquinoxaline is an important scaffold in the development of new potential effective and safer VEGFR-2 inhibitor agents.