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

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).

• Authors: 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
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 100 Pg. 89-97 (Jul 15 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26071861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

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

Topics

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