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

Gao，Zhenxiong1,2; Fan，Tingting2,3; Chen，Linbo2,3; Yang，Mengchu4; Wai Wong，Vincent Kam4; Chen，Dawei5,6; Liu，Zijian5,6; Zhou，Yaoyao2; Wu，Weibin5,6; Qiu，Zixuan2; Zhang，Cunlong5,6; Li，Yuan7; Jiang，Yuyang2,3,8,9

2022-08-05

10.1016/j.ejmech.2022.114402

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   影响因子和分区

0223-5234

1768-3254

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 T 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 G-S phase cell cycle arrest in liver cancer cells.

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

SCI

英语

通讯

Guangdong Science and Technology Department[2017B030314083];National Natural Science Foundation of China[81961160708];

Pharmacology & Pharmacy

Chemistry, Medicinal

WOS:000804189700004

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

CHEMISTRY

2-s2.0-85129280207

Scopus

1.Department of Chemical Engineering,Tsinghua University,Beijing,100084,China
2.State Key Laboratory of Chemical Oncogenomics,Guangdong Provincial Key Laboratory of Chemical Biology,Tsinghua Shenzhen International Graduate School,Shenzhen,518055,China
3.Department of Chemistry Southern University of Science and Technology,Shenzhen,518055,China
4.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
5.Shenzhen Kivita Innovat Drug Discovery Inst,Shenzhen,518057,China
6.Shenzhen Bay Bio-pharm Technology Co.,Ltd,Shenzhen,518057,China
7.The Collaborative Innovation Center for Cancer Personalized Medicine,School of Public Health,Nanjing Medical University,Nanjing,211166,China
8.Department of Pharmacology and Pharmaceutical Sciences,School of Medicine,Tsinghua University,Beijing,100084,China
9.Institute of Biomedical Health Technology and Engineering,Shenzhen Bay Laboratory,Shenzhen,518132,China

Gao，Zhenxiong,Fan，Tingting,Chen，Linbo,et al. Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,238.

Gao，Zhenxiong.,Fan，Tingting.,Chen，Linbo.,Yang，Mengchu.,Wai Wong，Vincent Kam.,...&Jiang，Yuyang.(2022).Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,238.

Gao，Zhenxiong,et al."Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 238(2022).