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

Esther C. Y. Woon; Peter T. Sunderland; Helen A. Paine; Matthew D. Lloyd; Andrew S. Thompson; Michael D. Threadgill

doi:10.1016/j.bmc.2013.06.031

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

Esther C. Y. Woon, Peter T. Sunderland, Helen A. Paine, Matthew D. Lloyd, Andrew S. Thompson, Michael D. Threadgill

Department of Life Sciences

National University of Singapore

Research output: Contribution to journal › Article › peer-review

21 Citations (SciVal)

256 Downloads (Pure)

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 language	English
Pages (from-to)	5218-5227
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	17
DOIs	https://doi.org/10.1016/j.bmc.2013.06.031
Publication status	Published - 1 Sept 2013

Keywords

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

Access to Document

10.1016/j.bmc.2013.06.031

Author's accepted version
NOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic & Medicinal Chemistry, vol 21, issue 17, 2013, DOI 10.1016/j.bmc.2013.06.031
Accepted author manuscript, 624 KB

Cite this

Woon, E. C. Y., Sunderland, P. T., Paine, H. A., Lloyd, M. D., Thompson, A. S., & Threadgill, M. D. (2013). 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. Bioorganic and Medicinal Chemistry, 21(17), 5218-5227. https://doi.org/10.1016/j.bmc.2013.06.031

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. / Woon, Esther C. Y.; Sunderland, Peter T.; Paine, Helen A. et al.
In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 17, 01.09.2013, p. 5218-5227.

Research output: Contribution to journal › Article › peer-review

Woon, ECY, Sunderland, PT , Paine, HA , Lloyd, MD , Thompson, AS & Threadgill, MD 2013, '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', Bioorganic and Medicinal Chemistry, vol. 21, no. 17, pp. 5218-5227. https://doi.org/10.1016/j.bmc.2013.06.031

@article{0abebeb8594c4c7b9f8dbb9b85692312,

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 = sep,

day = "1",

doi = "10.1016/j.bmc.2013.06.031",

language = "English",

volume = "21",

pages = "5218--5227",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier",

number = "17",

}

TY - JOUR

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.

PY - 2013/9/1

Y1 - 2013/9/1

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.

KW - PARP-1

KW - Hurtley reaction

KW - tandem

KW - isocoumarin

KW - isoquinolin-1-one

UR - http://www.scopus.com/inward/record.url?scp=84881370396&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1016/j.bmc.2013.06.031

U2 - 10.1016/j.bmc.2013.06.031

DO - 10.1016/j.bmc.2013.06.031

M3 - Article

SN - 0968-0896

VL - 21

SP - 5218

EP - 5227

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 17

ER -

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

Keywords

Access to Document

Other files and links

Fingerprint

MC2- Nuclear Magnetic Resonance (NMR)

Cite this

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

Keywords

Access to Document

Other files and links

Fingerprint

Equipment

MC2- Nuclear Magnetic Resonance (NMR)

Cite this