Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors

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• 作者：Xin Zhai^a ; ^{zhaixin_syphu@126.com" class="auth_mail" title="E-mail the corresponding author} ; Guanglong Bao^a ; Limei Wang^a ; Mingke Cheng^b ; Meng Zhao^a ; Sijia Zhao^a ; Hongyang Zhou^a ; Ping Gong^a ; ^{gongpinggp@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Quinoline ; (Thio)semicarbazone ; Anti-tumor activity ; c-Met kinase inhibitor ; Pharmacokinetic profile ; Xenograft mice model
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：24
• 期：6
• 页码：1331-1345
• 全文大小：1591 K

文摘

In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a–w, 26a–d and 30a–d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R² moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC₅₀ values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC₅₀ = 1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation.