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通往选择性PARP-2抑制剂之路。一系列异喹啉酮衍生物的设计、合成及初步评价。

On the way to selective PARP-2 inhibitors. Design, synthesis, and preliminary evaluation of a series of isoquinolinone derivatives.

作者信息

Pellicciari Roberto, Camaioni Emidio, Costantino Gabriele, Formentini Laura, Sabbatini Paola, Venturoni Francesco, Eren Gökçen, Bellocchi Daniele, Chiarugi Alberto, Moroni Flavio

机构信息

Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.

出版信息

ChemMedChem. 2008 Jun;3(6):914-23. doi: 10.1002/cmdc.200800010.

DOI:10.1002/cmdc.200800010
PMID:18409175
Abstract

PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.

摘要

聚（ADP-核糖）聚合酶家族中的PARP-1和PARP-2参与了遗传毒性刺激条件下基因组完整性的维持。两种异构体在病理生理条件下的不同作用尚未完全阐明，部分原因是缺乏选择性抑制剂。我们在此报告了一系列异喹啉酮衍生物作为PARP-1/PARP-2抑制剂的合成及初步药理评价。其中，我们鉴定出5-苯甲酰氧基异喹啉-1（2H）-酮衍生物是迄今为止报道的最具选择性的PARP-2抑制剂，其PARP-2/PARP-1选择性指数大于60。

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