新型蛋白质精氨酸甲基转移酶1（PRMT1）抑制剂4-((5-硝基嘧啶-4-基)氨基)苯并咪唑酰胺衍生物的发现与构效关系分析
Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.
作者信息
Yu Xu-Ri, Tang Yun, Wang Wen-Jing, Ji Sen, Ma Shuang, Zhong Lei, Zhang Chun-Hui, Yang Jiao, Wu Xiao-Ai, Fu Zheng-Yan, Li Lin-Li, Yang Sheng-Yong
机构信息
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
出版信息
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5449-53. doi: 10.1016/j.bmcl.2015.06.095. Epub 2015 Jul 3.
Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 μM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 μM, 13.1 μM and 11.4 μM, respectively.
尽管PRMT1抑制剂在癌症治疗中具有潜在应用，但已报道的PRMT1抑制剂却很少。为了获得新型强效PRMT1抑制剂，对一种先导化合物4-((6-氯-5-硝基嘧啶-4-基)氨基)苯并咪唑酰胺进行了结构优化。合成了一系列4-((5-硝基嘧啶-4-基)氨基)苯并咪唑酰胺衍生物。构效关系分析导致发现了多种PRMT1抑制剂。最有效的化合物是化合物6d，它对PRMT1的IC50值为2.0 μM。该化合物对三种肿瘤细胞系DLD-1、T24和SH-SY-5Y也表现出相当的抗增殖活性，IC50值分别为4.4 μM、13.1 μM和11.4 μM。
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