ABSTRACT
Vascular endothelial growth factor receptorâ 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell lines (MCF-7, HeLa, HepG2, and A549). Inâ vitro biological evaluations against these human tumor cell lines indicate that most of the prepared compounds have antiproliferative activities; compound 3 a (3ß-hydroxy-30-(4-phenyl-1-piperazinyl)olean-12-ene-11,30-dione) exhibited the best inhibitory activity against MCF-7 cells, with an IC50 value of 1.08â µm. Compound 3 a also showed the most potent inhibitory activity against VEGFR2 tyrosine kinase, with an IC50 value of 0.35â µm. Docking simulations were performed with the aim of discovering the binding mode of compound 3 a, and the results indicate that 3 a could bind at the VEGFR2 active site.
Subject(s)
Antineoplastic Agents/pharmacology , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/pharmacology , Piperazines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Glycyrrhetinic Acid/chemical synthesis , Glycyrrhetinic Acid/toxicity , Humans , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Piperazines/chemical synthesis , Piperazines/toxicityABSTRACT
A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC50 values of 0.46, 0.29, 0.15 and 0.21 µM respectively, which showed the most potent EGFR inhibition activities (IC50 = 0.08 µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent.