期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 18, 页码 4552-4557出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.06.054
关键词
Histone methyltransferase; Lysine specific demethylase 1 (LSD1); Conformational constraint; Anticancer
资金
- National ST Major project [2012ZX09501001-003]
- Program for New Century Excellent Talents in University [NSET-11-0360]
- Project of the National Natural Sciences Foundation of China [81272459, 81322035]
Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7 nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem. 2013, 56, 9496-9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study. (C) 2016 Published by Elsevier Ltd.
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