Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles.

Heba T. Abdel-Mohsen,Keith J. Flanagan,Mathias O. Senge,Mamdouh M. Ali,Ahmed M. El Kerdawy,Hoda I. El Diwani,Mona A. Abdullaziz,Abeer E. E. Mahmoud,Fatma A. F. Ragab

doi:10.3390/molecules25040770

Abstract

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

Highlights

Receptor tyrosine kinases (RTKs), a family of receptors that exist on the cell surface, play a crucial role in the cellular response to environmental signals [1]
25, 770 in a type2020, Against this background, we pursued our research through structural optimization of the 2furylbenzimidazole derivative IX by the design and synthesis of a novel series of VEGFR-2 inhibitors targeting hepatocellular carcinoma based on the benzimidazole scaffold
The first is to study the effect of replacing the 5-methylfuryl moiety at the two-position of IX with an isopropyl moiety in X on the hydrophobic interaction with the allosteric hydrophobic back pocket and further its impact on the VEGFR-2 inhibition; it could achieve a better accommodation of the benzimidazole moiety in the back pocket

Summary

Introduction

Receptor tyrosine kinases (RTKs), a family of receptors that exist on the cell surface, play a crucial role in the cellular response to environmental signals [1]. 770normal cells, RTK expression is highly regulated; in some pathological and survival. Conditions such as cancer there is an extreme up-regulation of some RTKs [2,3]. In this this respect, respect, the the vascular vascular endothelial endothelial growth growth factor factor receptor receptor (VEGFR).

Methods

Results

Conclusion