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Open AccessArticle

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

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Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, P.O. 12622, Cairo, Egypt
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Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt
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Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New Giza, km 22 Cairo–Alexandria Desert Road, Cairo, Egypt
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Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James’s Hospital, Dublin 8, Ireland
5
Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(4), 770; https://doi.org/10.3390/molecules25040770 (registering DOI)
Received: 16 January 2020 / Revised: 5 February 2020 / Accepted: 8 February 2020 / Published: 11 February 2020
(This article belongs to the Section Medicinal Chemistry)
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. View Full-Text
Keywords: design; synthesis; 1,2-disubstituted benzimidazole; VEGFR-2; angiogenesis; HepG-2 design; synthesis; 1,2-disubstituted benzimidazole; VEGFR-2; angiogenesis; HepG-2
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Abdel-Mohsen, H.T.; Abdullaziz, M.A.; El Kerdawy, A.M.; Ragab, F.A.F.; Flanagan, K.J.; Mahmoud, A.E.E.; Ali, M.M.; El Diwani, H.I.; 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, 25, 770.

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