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Bioorg Med Chem. 2013 Sep 1;21(17):5218-27. doi: 10.1016/j.bmc.2013.06.031. Epub 2013 Jun 22.

One-pot tandem Hurtley-retro-Claisen-cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs.

Author information

1
Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.

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.

KEYWORDS:

Hurtley reaction; Isocoumarin; Isoquinolin-1-one; PARP-1; Tandem

PMID:
23849206
DOI:
10.1016/j.bmc.2013.06.031
[Indexed for MEDLINE]

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