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

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ID: 96094
2020
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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 IC = 1.98 μM in comparison to sorafenib (IC = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds and showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of on the HepG2 cell cycle demonstrated that 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.
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abdelmohsen2020targetingmolecules Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Abdel-Mohsen, Heba T;Abdullaziz, Mona A;Kerdawy, Ahmed M El;Ragab, Fatma A F;Flanagan, Keith J;Mahmoud, Abeer E E;Ali, Mamdouh M;Diwani, Hoda I El;Senge, Mathias O;
Journal molecules
Year 2020
DOI
E770
URL
Keywords
synthesis VEGFR-2 design angiogenesis hepg-2 1,2-disubstituted benzimidazole

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