Drug Design, Development and Therapy (Mar 2022)
New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
Abstract
Abdallah E Abdallah,1 Reda R Mabrouk,1 Mohamed R Elnagar,2 Amel Mostafa Farrag,3 Mohamed H Kalaba,4 Mohamed H Sharaf,4 Esmail M El-Fakharany,5 Dina Abed Bakhotmah,6 Eslam B Elkaeed,7 Maged Mohammed Saleh Al Ward1 1Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt; 3Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt; 4Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt; 5Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications, New Borg El Arab, Egypt; 6Chemistry Department, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 7Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi ArabiaCorrespondence: Abdallah E Abdallah; Maged Mohammed Saleh Al Ward, Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt, Email [email protected]; [email protected]: 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 11, which was the most promising candidate.Results: The new derivatives revealed better antitumor results (IC50 from 6.48 to 38.58 μM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC50 values ranging from 0.19 to 0.60 μM compared to 0.08 μM for sorafenib. Compound 11, meanwhile, showed IC50 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 11 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 11 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.Keywords: anticancer, apoptosis, molecular modeling, piperazinylquinoxaline, VEGFR-2 kinase, Western blot
