Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors

Juan Sun; Shen-Zhen Ren; Xiao-Yuan Lu; Jing-Jing Li; Fa-Qian Shen; Chen Xu; Hai-Liang Zhu

doi:10.1016/j.bmc.2017.03.038

Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors

Bioorg Med Chem. 2017 May 1;25(9):2593-2600. doi: 10.1016/j.bmc.2017.03.038. Epub 2017 Mar 19.

Authors

Juan Sun¹, Shen-Zhen Ren², Xiao-Yuan Lu², Jing-Jing Li², Fa-Qian Shen², Chen Xu³, Hai-Liang Zhu⁴

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China; Jiangsu Naique Biological Engineering Technology Company Limited, Zhenjiang 212415, PR China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xuchn@nju.edu.cn.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China; Jiangsu Naique Biological Engineering Technology Company Limited, Zhenjiang 212415, PR China. Electronic address: zhuhl@nju.edu.cn.

PMID: 28363444
DOI: 10.1016/j.bmc.2017.03.038

Abstract

Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC₅₀=5.78μM for HepG2, and IC₅₀=47.15μM for SW1116), and its anti-FAK inhibitory activity (IC₅₀=0.78μM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site.

Keywords: Antitumor activity; Benzodioxan; FAK; Oxadiazoles; Piperazine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Dioxanes / chemical synthesis
Dioxanes / chemistry
Dioxanes / pharmacology*
Enzyme Assays
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Humans
Molecular Docking Simulation
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiones / chemical synthesis
Thiones / chemistry
Thiones / pharmacology*

Substances

5-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)-3-((4-(3(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,3,4-oxadiazole-2(3H)-thione
Antineoplastic Agents
Dioxanes
Oxadiazoles
Piperazines
Protein Kinase Inhibitors
Thiones
Focal Adhesion Kinase 1
PTK2 protein, human