Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2010, Vol.18 (1), p.314-319
• Main Authors: Lv, Peng-Cheng, Zhou, Chang-Fang, Chen, Jin, Liu, Peng-Gang, Wang, Kai-Rui, Mao, Wen-Jun, Li, Huan-Qiu, Yang, Ying, Xiong, Jing, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; EGFR; General aspects; HER-2; Humans; Inhibitors; Medical sciences; Models, Molecular; Neoplasms - drug therapy; Pharmacology. Drug treatments; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; SAR; Structure-Activity Relationship; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; Thiazolidinone derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.10.051

Compound 12 displayed the most potent inhibitory activity (IC 50 = 0.09 μM for EGFR and IC 50 = 0.42 μM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model and antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent. Two series of thiazolidinone derivatives designing for potential EGFR and HER-2 kinase inhibitors have been discovered. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4(5H)-one ( 12) displayed the most potent inhibitory activity (IC 50 = 0.09 μM for EGFR and IC 50 = 0.42 μM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.