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  3. Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs

  • Bioorg Chem. 2022 Apr;121:105672. doi: 10.1016/j.bioorg.2022.105672.
Pengqin Chen 1,  Ying Zhao 2,  Jianqing Zhang 3,  Yongli Duan 4,  Jintian Dai 3,  Jie He 2,  Xiemin Wang 1,  Xi Chen 2,  Pan Chen 1,  Weixin Zhao 2,  Xu Wang 2,  Zaishou Zhuang 5,  Daona Yang 5,  Guang Liang 6,  Qidong Tang 7
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
  • 3 School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, Jiangxi, China.
  • 4 School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, Jiangxi, China; School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China (UESTC), Chengdu 610054, Sichuan, China.
  • 5 The Affiliated Cangnan Hospital, Wenzhou Medical University, Cangnan 325800, Zhejiang, China.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang, China. Electronic address: cuiliang1234@163.com.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang, China; School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, Jiangxi, China. Electronic address: tangqidongcn@126.com.
PMID: 35202851 DOI: 10.1016/j.bioorg.2022.105672
Abstract

Giving the fact that the disorders of multiple Receptor Tyrosine Kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced Apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for Cancer therapy.

Keywords

6,7-Disubstituted-4-phenoxyquinoline derivatives; Antitumor activity; Molecular docking; Multi-target drugs; Tyrosine kinase inhibitors.

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