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

In this study, a novel series of 1,2-disubstituted benzo[<i>d</i>]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 an...

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Main Authors:	Heba T. Abdel-Mohsen, Mona A. Abdullaziz, Ahmed M. El Kerdawy, Fatma A. F. Ragab, Keith J. Flanagan, Abeer E. E. Mahmoud, Mamdouh M. Ali, Hoda I. El Diwani, Mathias O. Senge
Format:	Article
Language:	English
Published:	MDPI AG 2020-02-01
Series:	Molecules
Subjects:	design synthesis 1,2-disubstituted benzimidazole vegfr-2 angiogenesis hepg-2
Online Access:	https://www.mdpi.com/1420-3049/25/4/770

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spelling	doaj-d5681756020243118eccfbe786f072792020-11-25T02:38:23ZengMDPI AGMolecules1420-30492020-02-0125477010.3390/molecules25040770molecules25040770Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted BenzimidazolesHeba T. Abdel-Mohsen0Mona A. Abdullaziz1Ahmed M. El Kerdawy2Fatma A. F. Ragab3Keith J. Flanagan4Abeer E. E. Mahmoud5Mamdouh M. Ali6Hoda I. El Diwani7Mathias O. Senge8Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, P.O. 12622, Cairo, EgyptDepartment of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, P.O. 12622, Cairo, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, EgyptMedicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James’s Hospital, Dublin 8, IrelandDepartment of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, EgyptDepartment of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, EgyptDepartment of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, P.O. 12622, Cairo, EgyptMedicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James’s Hospital, Dublin 8, IrelandIn this study, a novel series of 1,2-disubstituted benzo[<i>d</i>]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<sub>50</sub> = 1.98 μM in comparison to sorafenib (IC<sub>50</sub> = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds <b>17a</b> and <b>6</b> showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of <b>17a</b> on the HepG2 cell cycle demonstrated that <b>17a</b> 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.https://www.mdpi.com/1420-3049/25/4/770designsynthesis1,2-disubstituted benzimidazolevegfr-2angiogenesishepg-2
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Heba T. Abdel-Mohsen Mona A. Abdullaziz Ahmed M. El Kerdawy Fatma A. F. Ragab Keith J. Flanagan Abeer E. E. Mahmoud Mamdouh M. Ali Hoda I. El Diwani Mathias O. Senge
spellingShingle	Heba T. Abdel-Mohsen Mona A. Abdullaziz Ahmed M. El Kerdawy Fatma A. F. Ragab Keith J. Flanagan Abeer E. E. Mahmoud Mamdouh M. Ali Hoda I. El Diwani Mathias O. Senge Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles Molecules design synthesis 1,2-disubstituted benzimidazole vegfr-2 angiogenesis hepg-2
author_facet	Heba T. Abdel-Mohsen Mona A. Abdullaziz Ahmed M. El Kerdawy Fatma A. F. Ragab Keith J. Flanagan Abeer E. E. Mahmoud Mamdouh M. Ali Hoda I. El Diwani Mathias O. Senge
author_sort	Heba T. Abdel-Mohsen
title	Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles
title_short	Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles
title_full	Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles
title_fullStr	Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles
title_full_unstemmed	Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles
title_sort	targeting receptor tyrosine kinase vegfr-2 in hepatocellular cancer: rational design, synthesis and biological evaluation of 1,2-disubstituted benzimidazoles
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2020-02-01
description	In this study, a novel series of 1,2-disubstituted benzo[<i>d</i>]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<sub>50</sub> = 1.98 μM in comparison to sorafenib (IC<sub>50</sub> = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds <b>17a</b> and <b>6</b> showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of <b>17a</b> on the HepG2 cell cycle demonstrated that <b>17a</b> 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.
topic	design synthesis 1,2-disubstituted benzimidazole vegfr-2 angiogenesis hepg-2
url	https://www.mdpi.com/1420-3049/25/4/770
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Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

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