Targeting receptor tyrosine kinase VEGFR-2 in hepatocellular cancer: Rational design, synthesis and biological evaluation of 1,2-disubstituted benzimidazoles
Citation:
Abdel-Mohsen, H.T., Abdullaziz, M.A,, Kerdawy, A.M.E., Ragab, F.A.F., Flanagan, K.J., Mahmoud, A.E.E., Ali, M.M., Diwani, H.I.E., Senge, M.O., Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles. Molecules, 2020 Feb 11;25(4):770Download Item:
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.
Sponsor
Grant Number
Science Foundation Ireland
IvP 13/IA/1894
Author's Homepage:
http://people.tcd.ie/sengem
Author: Senge, Mathias
Type of material:
Journal ArticleCollections
Series/Report no:
Molecules;25;
4;
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Full text availableKeywords:
1,2-disubstituted benzimidazole, HepG-2, VEGFR-2, Angiogenesis, Design, SynthesisDOI:
http://dx.doi.org/10.3390/molecules25040770Metadata
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