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

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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 = 0.23 M vs IC50 = 1.6 M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.

Original languageEnglish
Pages (from-to)5218-5227
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
Publication statusPublished - 1 Sep 2013

Fingerprint

Cyclization
3-nitrobenzoic acid
Poly(ADP-ribose) Polymerases
Water
Lead compounds
Molecular modeling
Tin
Ammonia
Chlorides
Salts
Pharmaceutical Preparations
5-aminoisoquinoline
Poly(ADP-ribose) Polymerase Inhibitors
Temperature

Keywords

  • PARP-1
  • Hurtley reaction
  • tandem
  • isocoumarin
  • isoquinolin-1-one

Cite this

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title = "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",
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 = 0.23 M vs IC50 = 1.6 M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.",
keywords = "PARP-1, Hurtley reaction, tandem, isocoumarin, isoquinolin-1-one",
author = "Woon, {Esther C. Y.} and Sunderland, {Peter T.} and Paine, {Helen A.} and Lloyd, {Matthew D.} and Thompson, {Andrew S.} and Threadgill, {Michael D.}",
year = "2013",
month = "9",
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T1 - 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

AU - Woon, Esther C. Y.

AU - Sunderland, Peter T.

AU - Paine, Helen A.

AU - Lloyd, Matthew D.

AU - Thompson, Andrew S.

AU - Threadgill, Michael D.

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N2 - 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 = 0.23 M vs IC50 = 1.6 M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.

AB - 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 = 0.23 M vs IC50 = 1.6 M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.

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