AI Article Synopsis
- Poly(ADP-ribose)polymerase-1 (PARP-1) is a key target for drug development, with research focusing on creating new inhibitors.
- A highly soluble compound, 5-Aminoisoquinolin-1-one (5-AIQ), was used to explore synthetic pathways that led to 3-substituted analogues, resulting in a series of water-soluble 5-nitroisocoumarins.
- The resulting 3-substituted 5-AIQs were found to be more effective than 5-AIQ itself in inhibiting PARP-1 and PARP-2, with the most potent compound showing an IC50 of 0
Article Abstract
Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of β-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50=0.23μM vs IC50=1.6μM for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.
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| http://dx.doi.org/10.1016/j.bmc.2013.06.031 | DOI Listing |
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