期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 22, 页码 5449-5453出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.06.095
关键词
PRMT1; Small molecule inhibitor; Epigenetics; Structure-activity relationship; Protein arginine methyltransferase
资金
- 863 Hi-Tech Program [2012AA020301, 2012AA020308]
- National Natural Science Foundation of China [81172987, 81325021, 81473140]
- National Science and Technology Major Project [2012ZX09501001-003, 2012ZX09102-101-002]
- SRFDP [20100181110025]
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 mu M 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 mu M, 13.1 mu M and 11.4 mu M, respectively. (C) 2015 Elsevier Ltd. All rights reserved.
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