摘要
5-氨基异喹啉-1-酮(5-AIQ)(5-AIQ)是一种水溶性的聚(ADP核糖)聚合酶(PARP抑制剂),但其缺乏亚型选择性。虽然抗PARP-1体外活性温和,但其在体内许多模型实验中活性很高,且具有良好的吸收。对5-AIQ几种合成序列进行优化,可从1-氯异喹啉开始一个高效短程的发展路径。其已被广泛地用于生化和药理研究工具,如研究PARP的抑制作用,可改善细胞和组织缺血后再灌注损伤,在低剂量30 µg Kg-1失血性休克动物模型中表现出明显的保护作用。在心肌梗死、缺血性肾、肝功能、脑卒及器官移植模型中也有保护作用。通过5-AIQ抑制PARP-1引起NF-κB的活性下调,从而引起几个基因产物的表达下调。因此,5-AIQ通过调节体内细胞因子和粘附分子的表达产生抗炎活性。在关节炎,帕金森病,多发性硬化症,脊髓损伤,牙周炎,肺炎模型中,这种表达的间接抑制与5-AIQ活性有关。金属蛋白酶基质的表达抑制,在小鼠模型中,其他因素引起抗血管生成活性增加和显著的抗肿瘤活性。因此,尽管在肿瘤临床诊断中,其已超越了其他PARP抑制药物,5-AIQ仍为研究PARP在健康和各种疾病人体中发挥作用的一个有用工具。
关键词: 5-AIQ,5-氨基异喹啉-1-酮(5-AIQ),癌症,炎症,缺血再灌注损伤,转移,NF-κBκ,聚(ADP-核糖)聚合酶
Current Medicinal Chemistry
Title:5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs)
Volume: 22 Issue: 33
Author(s): Michael D. Threadgill
Affiliation:
关键词: 5-AIQ,5-氨基异喹啉-1-酮(5-AIQ),癌症,炎症,缺血再灌注损伤,转移,NF-κBκ,聚(ADP-核糖)聚合酶
摘要: 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.
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Cite this article as:
Michael D. Threadgill , 5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs), Current Medicinal Chemistry 2015; 22 (33) . https://dx.doi.org/10.2174/0929867322666151002110602
DOI https://dx.doi.org/10.2174/0929867322666151002110602 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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