Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein

  • Eur J Med Chem. 2022 Aug 5;238:114402. doi: 10.1016/j.ejmech.2022.114402.
Zhenxiong Gao  1 ,  Tingting Fan  2 ,  Linbo Chen  2 ,  Mengchu Yang  3 ,  Vincent Kam Wai Wong  3 ,  Dawei Chen  4 ,  Zijian Liu  4 ,  Yaoyao Zhou  5 ,  Weibin Wu  4 ,  Zixuan Qiu  5 ,  Cunlong Zhang  6 ,  Yuan Li  7 ,  Yuyang Jiang  8
Affiliations
  • 1. Department of Chemical Engineering, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China.
  • 2. State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China.
  • 3. Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
  • 4. Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen, 518057, PR China; Shenzhen Bay Bio-pharm Technology Co., Ltd, Shenzhen, 518057, PR China.
  • 5. State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China.
  • 6. Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen, 518057, PR China; Shenzhen Bay Bio-pharm Technology Co., Ltd, Shenzhen, 518057, PR China. Electronic address: [email protected].
  • 7. The Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. Electronic address: [email protected].
  • 8. State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China. Electronic address: [email protected].
PMID: 35525080 DOI: 10.1016/j.ejmech.2022.114402
Abstract

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver Cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver Cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-Fu cells. Besides, C11 was rather safe against hERG and possessed moderate T1/2 and CL values in liver microsomes. In anti-proliferation, trans-well and cell Apoptosis assays, C11 also showed its huge potential as a potent antitumor agent. Then, Western blot assay was conducted, following analyzed by molecular docking, the anti-proliferative mechanisms of this small-molecule inhibitor were revealed. Moreover, C11 was demonstrated to induce G1-S phase cell cycle arrest in liver Cancer cells.

Keywords
14-3-3η protein; Antitumor bioactivity; Drug design; Hepatocellular carcinoma; Novel target.
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