Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 11; pp. 3812 - 3822
• Main Authors: Wu, Xiaoqing, Li, Mingdong, Qu, Yang, Tang, Wenhua, Zheng, Youguang, Lian, Jiqin, Ji, Min, Xu, Liang
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2010; Elsevier
• Subjects: 4-Benzothienyl amino quinazolines; Antineoplastic agents; Antineoplastic Agents - chemistry; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cancer cells; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Design; Gefitinib; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - therapeutic use; Receptor tyrosine kinase; Receptor, Epidermal Growth Factor; Receptor, ErbB-2; Gefitinib; Antineoplastic agent; Quinazoline derivatives; Receptor tyrosine kinase; Benzothiophene derivatives; Signal transduction; Cancer cells; Receptor protein-tyrosine kinase; Pancreas; Chemical synthesis; Tumor cell; Gefitinib, 4-Benzothienyl amino quinazolines; Human; Enzyme; Transferases; Rodentia; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; Apoptosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.046

Two series of 4-benzothienyl amino quinazolines were designed and synthesized as new analogues of the EGFR inhibitor Gefitinib, with improved anti-tumor and pro-apoptotic activity. There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.