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

被引：5

作者：

Gao, Zhenxiong ^{[1
,2
]}

Fan, Tingting ^{[2
,3
]}

Chen, Linbo ^{[2
,3
]}

Yang, Mengchu ^{[4
]}

Wong, Vincent Kam Wai ^{[4
]}

Chen, Dawei ^{[5
,6
]}

Liu, Zijian ^{[5
,6
]}

Zhou, Yaoyao ^{[2
]}

Wu, Weibin ^{[5
,6
]}

Qiu, Zixuan ^{[2
]}

Zhang, Cunlong ^{[5
,6
,10
]}

Li, Yuan ^{[7
]}

Jiang, Yuyang ^{[2
,3
,8
,9
]}

机构：

[1] Tsinghua Univ, Dept Chem Engn, Beijing 100084, Peoples R China

[2] Tsinghua Shenzhen Int Grad Sch, State Key Lab Chem Oncogen, Guangdong Prov Key Lab Chem Biol, Shenzhen 518055, Peoples R China

[3] Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China

[4] Macau Univ Sci & Technol, Dr Nehers Biophys Lab Innovat Drug Discovery, State Key Lab Qual Res Chinese Med, Macau, Peoples R China

[5] Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen 518057, Peoples R China

[6] Shenzhen Bay Biopharm Technol Co Ltd, Shenzhen 518057, Peoples R China

[7] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Sch Publ Hlth, Nanjing 211166, Peoples R China

[8] Tsinghua Univ, Sch Med, Dept Pharmacol & Pharmaceut Sci, Beijing 100084, Peoples R China

[9] Inst Biomed Hlth Technol & Engn, Shenzhen Bay Lab, Shenzhen 518132, Peoples R China

[10] Shenzhen Bay Biopharm Technol Co Ltd, Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen 518057, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 238卷

基金：

中国国家自然科学基金;

关键词：

Hepatocellular carcinoma; 14-3-3? protein; Novel target; Drug design; Antitumor bioactivity; HEPATOCELLULAR-CARCINOMA; ACTIVATION; INHIBITORS; SORAFENIB; DISCOVERY;

D O I：

10.1016/j.ejmech.2022.114402

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3 eta protein were designed and synthesized for treatment of liver cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3 eta, 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, transwell 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.

引用

页数：15

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