Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 15, Pages 4045-4054Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.05.052
Keywords
Quinazoline-2,4(1H,3H)-dione; PARP-2 selective inhibitor; Anti-tumor agents
Funding
- National Natural Science Foundation of China [81673300]
- PUMC Graduate Innovation Fund [2015-1007-10]
- PUMC Innovation Fund [2016-12 M-3-008]
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The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50 = 467 nM, PARP-2 IC50 = 11.5 nM, selectivity PARP-1/PARP-2 = 40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program. (C) 2017 Elsevier Ltd. All rights reserved.
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