2. Academic Validation
  3. The lead optimization of the polyamine conjugate of flavonoid with a naphthalene motif: Synthesis and biological evaluation

The lead optimization of the polyamine conjugate of flavonoid with a naphthalene motif: Synthesis and biological evaluation

  • Eur J Med Chem. 2018 Feb 25:146:564-576. doi: 10.1016/j.ejmech.2018.01.074.
Qian Li 1,  Zi-Xin Zhu 1,  Xin Zhang 1,  Wen Luo 2,  Li-Ping Chang 1,  Shuai Chen 1,  Yu-Xia Wang 3,  Song-Qiang Xie 4,  Cong-Cong Chang 1,  Chao-Jie Wang 5
Affiliations

Affiliations

  • 1 Key Lab of Natural Medicine and Immune Engineering, Henan University, Kaifeng 475004, China.
  • 2 Key Lab of Natural Medicine and Immune Engineering, Henan University, Kaifeng 475004, China; Institute of Chemical Biology, Henan University, Kaifeng 475004, China. Electronic address: luowen83@henu.edu.cn.
  • 3 Chemistry Department, Henan University, Kaifeng 475004, China. Electronic address: wangyuxia@henu.edu.cn.
  • 4 Institute of Chemical Biology, Henan University, Kaifeng 475004, China.
  • 5 Key Lab of Natural Medicine and Immune Engineering, Henan University, Kaifeng 475004, China. Electronic address: wcjsxq@henu.edu.cn.
PMID: 29407981 DOI: 10.1016/j.ejmech.2018.01.074
Abstract

Polyamine conjugated flavonoid with a naphthalene moiety (ZYY14) displayed excellent therapeutic activity against hepatocellular carcinoma. In this study, three different series of novel flavonoid-polyamine conjugates were designed and screened against tumor cell lines. The structure-activity relationship study demonstrated the importance of the naphthalene moiety (as the B-ring), the basic side chains in the A-ring, and the methoxy group linked to the C-ring. The optimized compound 9b displayed better antitumor potency in vitro and in vivo than the lead compound ZYY14. Fluorescent assays revealed that 9b could enter Cancer cells via polyamine transporter (PAT) and locate in mitochondria and endoplasmic reticulum. Compound 9b and ZYY14 demonstrated similar apoptotic mechanism in the cytotoxicity studies and stimulated the expression of apoptosis-related proteins, such as p-p38, p-JNK, p53 and Bax. In addition, 9b can initiate Autophagy which inhibited the occurrence of Apoptosis. Thus, 9b can be used as a valuable lead for the future development of antitumor agents.

Keywords

Antitumor; Apoptosis; Autophagy; Flavonoids; Polyamine.

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