Indoline ureas as potential anti-hepatocellular carcinoma agents targeting VEGFR-2: Synthesis, in vitro biological evaluation and molecular docking

Wagdy M Eldehna; Mohamed Fares; Hany S Ibrahim; Mohamed H Aly; Suher Zada; Mamdouh M Ali; Sahar M Abou-Seri; Hatem A Abdel-Aziz; Dalal A Abou El Ella

doi:10.1016/j.ejmech.2015.05.040

Indoline ureas as potential anti-hepatocellular carcinoma agents targeting VEGFR-2: Synthesis, in vitro biological evaluation and molecular docking

Eur J Med Chem. 2015 Jul 15:100:89-97. doi: 10.1016/j.ejmech.2015.05.040. Epub 2015 May 31.

Authors

Wagdy M Eldehna¹, Mohamed Fares², Hany S Ibrahim², Mohamed H Aly³, Suher Zada⁴, Mamdouh M Ali⁵, Sahar M Abou-Seri⁶, Hatem A Abdel-Aziz⁷, Dalal A Abou El Ella⁸

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt. Electronic address: wagdy2000@gmail.com.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt; Department of Biology, The American University in Cairo, P.O. Box 11835, New Cairo, Egypt.
⁴ Department of Biology, The American University in Cairo, P.O. Box 11835, New Cairo, Egypt.
⁵ Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622 Giza, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt. Electronic address: hatem_741@yahoo.com.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt.

PMID: 26071861
DOI: 10.1016/j.ejmech.2015.05.040

Abstract

In our effort to develop potent and effective agents with anti-proliferative activity towards HepG2 hepatocellular carcinoma cells with potential inhibitory activity against VEGFR-2, a novel series of 1-(4-((2-oxoindolin-3-ylidene)amino)phenyl)-3-arylureas was designed and synthesized. All the newly prepared ureas 9a-x were evaluated in vitro for their anti-proliferative activity against HepG2 hepatocellular carcinoma cell line. Compounds 9a-c, 9e, 9f, 9j, 9m-o, 9t-v and 9x exhibited good activity against HepG2 cancer cells (IC50 = 1.22 ± 0.11-8.37 ± 0.85 μM) comparable to that of doxorubicin and sorafinib (IC50 = 2.90 ± 0.36 and 3.40 ± 0.25 μM, respectively). These thirteen compounds were further evaluated for their inhibitory activity against VEGFR-2. Compound 9x emerged as the most active counterpart against VEGFR-2 with IC50 value of 0.31 ± 0.04 μM. Furthermore, a molecular docking of the tested compounds was carried out in order to investigate their binding pattern with the prospective target, VEGFR-2 (PDB-code: 4ASD).

Keywords: Design; Docking; HepG2; Urea; VEGFR-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Liver Neoplasms / drug therapy*
Liver Neoplasms / pathology
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Urea
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2