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

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

  • Bioorg Med Chem. 2016 Mar 15;24(6):1331-45. doi: 10.1016/j.bmc.2016.02.003.
Xin Zhai 1 Guanglong Bao 2 Limei Wang 2 Mingke Cheng 3 Meng Zhao 2 Sijia Zhao 2 Hongyang Zhou 2 Ping Gong 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhaixin_syphu@126.com.
  • 2 Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 3 Chong Qing Yaopharma CO., LTD, Chongqing 401121, PR China.
  • 4 Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
Abstract

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 R(2) 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.

Keywords

(Thio)semicarbazone; Anti-tumor activity; Pharmacokinetic profile; Quinoline; Xenograft mice model; c-Met kinase inhibitor.

Figures