"Synthesis and biological evaluation of novel 2,4-dianilinopyrimidine derivatives as potent dual janus kinase 2 and histone deacetylases inhibitors"

作者全名："Zhou, Haiping; Jiang, Junhao; Lu, Jinyu; Ran, Dongzhi; Gan, Zongjie"

作者地址："[Zhou, Haiping; Lu, Jinyu] Changzhou Inst Engn Technol, Coll Chem & Pharmaceut Engn, Changzhou 213000, Peoples R China; [Jiang, Junhao; Ran, Dongzhi; Gan, Zongjie] Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China"

通信作者："Gan, ZJ (通讯作者)，Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China."

来源：JOURNAL OF MOLECULAR STRUCTURE

ESI学科分类：CHEMISTRY

WOS号：WOS:000780918500007

JCR分区：Q3

影响因子：3.8

年份：2022

卷号：1253

期号：　

开始页：　

结束页：　

文献类型：Article

关键词："Dual JAK2-HADC inhibitors; 2,4-Dianilinopyrimidine derivatives; Antiproliferation; Apoptosis; Cell cycle"

摘要："Dual or multiple-targeting inhibition of oncogenic targets in a single molecule could be an alternative approach to drug combinations. Previous studies have revealed that histone deacetylases (HDAC) inhibitor in combination with janus kinase (JAK) inhibitor could exhibit synergistically anti-proliferative effects in cancer treatment. Herein, we presented a novel series of 2,4-dianilinopyrimidine derivatives, which could simultaneously inhibit JAK2 and HDAC1. Among which, 7l was found to be the most potent compound and displayed balanced inhibitory activity against HDAC1 (IC50 = 1.9 nM) and JAK2 (IC50 = 0.5 nM), respectively. 7l also demonstrated good antiproliferative activity against tested cancer cell lines (A549, HepG-2, MDA-MB-231 and Jurkat). Moreover, flow cytometric analysis showed that 7l induced apoptosis and cell cycle arrest in a dose-dependent manner, and the insight into mechanisms of 7l indicated that it could decrease the phosphorylation of STAT-3 and promote histone acetylation. In conclusion, these results together suggested that 7l would be a promising lead candidate and deserved further research and development. (c) 2021ElsevierB.V. Allrightsreserved."

基金机构：National Natural Science Foundation of China [21907013]; Applied Basic Research Science and Technology Plan of Changzhou [CJ20190019]

基金资助正文：This work was supported by National Natural Science Foundation of China (No. 21907013) and Applied Basic Research Science and Technology Plan of Changzhou (No. CJ20190019)