5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs)

Abstract

5-Aminoisoquinolin-1-one (5-AIQ) is a water-soluble inhibitor of the poly(ADPribose) 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 µg 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-κB, 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.

An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy

“…Phthalazinones belong to the earliest PARP inhibitors and were first reported by Banasik and Ueda in 1992. , Although the early compounds showed low potency, subsequent structural modification on this framework yielded numerous potent PARP inhibitors, including the first-in-class PARP inhibitor 2 .…”

Magnetic Thermoresponsive Nanocomposite for Targeted PARP-1 in Colorectal Adenocarcinoma, an Approach for Tumor Dual Therapy

“…PARP-1 belongs to the superfamily of more than seventeen enzymes that catalyzes the transfer of ADP-ribose units from its substrate NAD + to several protein acceptors as single-strand break repair and base excision repair factors, which contribute to DNA repair (Watson, Whish, & Threadgill, 1998), (Ba & Garg, 2011). In general, PARP inhibitors act through competitive blocking of the NAD + binding domain of the enzyme (Virág & Szabó, 2002); the effect which inhibits the repair of damaged DNA and facilitates apoptosis-dependent death of tumor cells (Threadgill, 2015). 5aminoisoquinoline (5-AIQ) is an active, water soluble inhibitor of Poly (ADP-ribose) polymerase-1 (PARP-1) and adjunctly promotes radiotherapy and chemotherapy of various cancer types (Vinod, Chandra, & Sharma, 2010), (Cuzzocrea et al, 2002).…”

PARP Inhibitors: A Breakthrough in Cancer Chemotherapy

“…To support this hypothesis several hetero cycles has been developed and all these molecules were found potent PARP inhibitors. This work has helped in the development of clinically relevant PARP inhibitors [14].…”