新型吲哚类SIRT2抑制剂的设计、合成及生物活性研究

SIRT2是Surtuin（SIRT）蛋白7种亚型的1种非典型去乙酰化酶，它的异常与癌症、神经退行性疾病、细菌感染等疾病的发生、发展密切相关。目前，虽有大量的SIRT2小分子抑制剂被陆续报道，但仍无抑制剂进入临床研究。本文前期研究获得了1个具有潜在SIRT2抑活性的化合物N-（1-苄基-1H-吲唑-4-基）-2-（萘-1-基氧基）乙酰胺（14a），在100和10 μmol·L?1浓度下，分别表现出了70%和36%的抑制率。本文通过对化合物14a进行结构修饰，根据生物电子等排体原理将吲唑环的2位N原子用C原子代替而成吲哚环，然后再在吲哚环1-N上引入疏水基团，设计并合成了一系列新型吲哚类目标化合物，通过酶水平活性评价获得了具有较好抑制活性的化合物27m。本文的研究为靶向SIRT2的抗肿瘤药物研究提供了更多的SIRT2新骨架。

Design,Synthesis and Biological Activity Evaluation of Novel Indole SIRT2 Inhibitors

SIRT2, an atypical deacetylase, belongs to one of the seven subtypes of Surtuin protein, which plays an important role in the occurrence and development of cancer, neurodegenerative diseases, bacterial infections and other diseases. Nowadays, a large number of SIRT2 small molecule inhibitors have been reported one after another, but so far no inhibitor has entered clinical research. In our previous research, through rational design and synthesis, N-(1-benzyl-1H-indazol-4-yl)-2-(naphthalen-1-yloxy)acetamide(14a), a SIRT2 inhibitor with potent inhibitory activity was obtained. It has an seperately inhibition rate of 70% and 36% at 100 μmol·L?1 and 10 μmol·L?1. Starting from compound 14a, after replacing the N atom at the position with a C atom, 10 new N- (1 H- indole-4-yl) -2- (naphthalene -1-oxyl) acetamides derivatives were designed and synthesized. A series of rational drug design and novel indindl target compounds were designed and synthesized, and 27m of better inhibitory activity were obtained by enzyme-level activity evaluation . The research in this paper provided more new SIRT2 frameworks for the development of SIRT2 inhibitors.