Discovery and structure–activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5449
• Page End: 5453
• Publication Date: 2015-11-15
• Subjects: PRMT1 -- Small molecule inhibitor -- Epigenetics -- Structure–activity relationship -- Protein arginine methyltransferase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.06.095
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 compound6d, 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.