5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs)
5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs)
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DOI：
10.2174/0929867322666151002110602
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发表时间：
2015-01-01
影响因子：
4.1
通讯作者：
Threadgill, Michael D.
中科院分区：
文献类型：
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作者：
Threadgill, Michael D.
5-氨基异喹啉-1-酮（5-AIQ）是聚（ADP-核糖）聚合酶（PARP）的水溶性抑制剂，缺乏异构体选择性。尽管在体外对PARP-1仅具有中等效力，但在细胞和体内模型中的许多试验中具有高度活性，表明吸收良好。对5-AIQ的几种合成序列的优化导致了从1-氯异喹啉开始的短而有效的路线的开发。它已被广泛用作研究PARP抑制作用的生物化学和药理学工具。它能改善缺血组织再灌注后细胞和组织的损伤，在啮齿动物出血性休克模型中，以30 μ g/Kg（-1）的极低剂量显示出显著的保护活性。在心肌梗死、缺血性肾脏和肝脏疾病、中风和器官移植模型中也观察到保护作用。5-AIQ对PARP-1的抑制导致NF-κ B活性的下调，NF-κ B随后下调几种基因产物的表达。因此，5-AIQ通过调节细胞因子和粘附分子的表达而具有体内抗炎活性。这种表达的间接抑制与5-AIQ在关节炎、帕金森病、多发性硬化、脊髓损伤、牙周炎和肺部炎性疾病模型中的活性有关。抑制基质金属蛋白酶和其他因子的表达在小鼠模型中产生抗血管生成活性和显著的抗转移活性。因此，尽管在肿瘤临床中它已被其他PARP抑制药物所取代，但5-AIQ仍然是研究PARP在健康和各种疾病中作用的有价值的工具。
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 mu 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-kappa B, 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.