Design, synthesis and biological evaluation of sulfonamide-substituted diphenylpyrimidine derivatives (Sul-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with antitumor activity

被引：31
作者：
Qu, Menghua [1 ]
Liu, Zhihao [1 ]
Zhao, Dan [1 ]
Wang, Changyuan [1 ]
Zhang, Jianbin [1 ]
Tang, Zeyao [1 ]
Liu, Kexin [1 ]
Shu, Xiaohong [1 ]
Yuan, Hong [2 ]
Ma, Xiaodong [1 ]
机构：
[1] Dalian Med Univ, Coll Pharm, Dalian 116044, Peoples R China
[2] Dalian Med Univ, Affiliated Hosp 1, Clin Lab, Dalian 116011, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 15期
基金：
中国国家自然科学基金;
关键词：
Cancer; FAK; Inhibitor; Pyrimidine; Sulfonamide; IN-VIVO; CANCER; DISCOVERY; CELLS; ASSAY;
D O I：
10.1016/j.bmc.2017.05.044
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A class of sulfonamide-substituted diphenylpyrimidines (Sul-DPPYs) were synthesized to improve activity against the focal adhesion kinase (FAK). Most of these new Sul-DPPYs displayed moderate activity against the FAK enzyme with IC50 values of less than 100 nM; regardless, they could effectively inhibit several classes of refractory cancer cell lines with IC50 values of less than 10 mu M, including the pancreatic cancer cell lines (AsPC-1, Panc-1 and BxPC-3), the NSCLC-resistant H1975 cell line, and the B lymphocyte cell line (Ramos cells). Results of flow cytometry indicated that inhibitor 7e promoted apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, it almost completely induced the apoptosis at a concentration of 10 mu M. Compound 7e may be selected as a potent FAK inhibitor for the treatment of pancreatic cancer. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3989 / 3996
页数：8
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