5-Aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of the poly(ADP-ribose)polymerases (PARPs)

Research output: Contribution to journalLiterature review

2 Citations (Scopus)

Abstract

5-Aminoisoquinolin-1-one (5-AIQ) is a water-soluble inhibitor of the poly(ADP-ribose)polymerases (PARPs), lacking isoform-selectivity. Although of only moderate potency in vitro against PARP-1, it is highly active in many assays in cells and in models in vivo, indicating excellent uptake. Optimisation of the several synthetic sequences to 5-AIQ has led to development of a short and efficient route from 1-chloroisoquinoline. It has been used widely as a biochemical and pharmacological tool to study the effects of inhibition of the PARPs. It ameliorates the damage to cells and tissues following reperfusion of ischaemic tissue, showing significant protective activity in a rodent model of haemorrhagic shock at the remarkably low dose of 30 micro g Kg-1. Protection is also seen in models of myocardial infarction, ischaemic kidney and liver disorders, stroke and organ transplantation. Inhibition of PARP-1 by 5-AIQ causes down-regulation of the activity of NF-kappaB, which then down-regulates the expression of several gene products. Thus 5-AIQ has anti-inflammatory activity in vivo, through modulating the expression of cytokines and adhesion molecules. This indirect inhibition of expression is relevant in the activity of 5-AIQ in models of arthritis, Parkinson’s disease, multiple sclerosis, spinal cord injury, periodontitis and inflammatory conditions of the lung. Inhibition of expression of matrix metalloproteinases and other factors gives rise to anti-angiogenic activity and to remarkable anti-metastatic activity in a mouse model. Thus, although it has been overtaken by other PARP-inhibiting drugs in the oncological clinic, 5-AIQ remains a valuable tool to study the roles of PARPs in health and in diverse diseases.
LanguageEnglish
Pages3807-3829
JournalCurrent Medicinal Chemistry
Volume22
Issue number33
StatusPublished - Nov 2015

Fingerprint

Poly(ADP-ribose) Polymerases
Water
Down-Regulation
Hemorrhagic Shock
NF-kappa B
Periodontitis
Organ Transplantation
Matrix Metalloproteinases
Spinal Cord Injuries
Liver Transplantation
Multiple Sclerosis
Reperfusion
Arthritis
Parkinson Disease
Poly(ADP-ribose) Polymerase Inhibitors
5-aminoisoquinoline
Rodentia
Protein Isoforms
Anti-Inflammatory Agents
Stroke

Cite this

5-Aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of the poly(ADP-ribose)polymerases (PARPs). / Threadgill, Michael D.

In: Current Medicinal Chemistry, Vol. 22, No. 33, 11.2015, p. 3807-3829.

Research output: Contribution to journalLiterature review

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