Citation: Guan Daokun, Sun Shaofeng, Chen Jing, He Zuopeng, Kong Xiangkai, Wang Ningning, Yao Jianwen, Wang Hongbo. Synthesis and Evaluation of Antitumor Activity of Sorafenib Derivatives Possessing Diphenylamine and Thiourea Structures[J]. Chinese Journal of Organic Chemistry, ;2018, 38(6): 1414-1421. doi: 10.6023/cjoc201802005 shu

Synthesis and Evaluation of Antitumor Activity of Sorafenib Derivatives Possessing Diphenylamine and Thiourea Structures

Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University, Yantai 264005

Corresponding author: Yao Jianwen, jwyao@ytu.edu.cn Wang Hongbo, hongbowangwt@gmail.com
Received Date: 2 February 2018
Revised Date: 22 March 2018
Available Online: 13 June 2018
Fund Project: the Key Technology Development Plan of Yantai City 2017ZH075the Key Research Project of Shandong Province 2017GSF18177the National Natural Science Foundation of 81728020Project supported by the National Natural Science Foundation of China (No. 81728020), the Key Research Project of Shandong Province (No. 2017GSF18177), and the Key Technology Development Plan of Yantai City (No. 2017ZH075)

Figures(4)

17 novel sorafenib derivatives possessing diphenylamine and thiourea structures were designed and synthesized using 2-picolinic acid and substituted anilines as raw materials. The structures of the target compounds were all characterized by NMR and HRMS. In addition, the in vitro antiproliferation activity of the target compounds was studied in human colon cancer cell HCT116, human breast cancer cell line MDA-MB-231, human prostate cancer cell line PC-3 and mouse melanoma cell line B16BL6. The results showed that 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-(2-(isopropylcarbamoyl)pyridine-4-amino)phenyl)thiourea (9g) had better inhibitory activity against four cell lines than the positive drug sorafenib, and 1-(3-trifluoromethyl-4-chlorophenyl)-3-{4-[2-(methylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9b) and 1-(3-trifluoro-methyl-4-fluorophenyl)-3-{4-[2-(isopropylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9j) had better inhibitory activity against MDA-MB-231, PC-3 and B16BL6 cell lines. The molecular docking of the active small molecule 9j was further studied, and its binding mode with the active site of the 3-D crystal structure (5HI2) of B-Raf receptor was discussed, which provided a useful reference for the design and synthesis of novel sorafenib derivatives in the future.
- B-Raf,
- molecular docking,
- an-titumor activity,
- diphenylamine and thiourea,
- sorafenib derivatives
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