A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors
A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors
复制标题
DOI：
10.1002/anie.201507985
复制
发表时间：
2015-12-14
影响因子：
16.6
通讯作者：
Britton, Robert
中科院分区：
文献类型：
--
作者：
Bergeron-Brlek, Milan;Goodwin-Tindall, Jake;Britton, Robert
吡咯烷基亚胺环醇是一类很有前途的糖苷酶抑制剂。本文报道了一种方便的异构化策略，它提供了直接获得O-GlcNAcase(OGA)的一系列立体异构体亚胺环胞醇抑制剂(OGA)的途径，该酶负责催化从核质蛋白中去除O-GlcNAc。关于这些抑制剂与OGA细菌同系物结合的结构细节揭示了效力的基础。这些化合物是口服的，可以渗透到啮齿动物的大脑中，增加O-GlcNAc，应该被证明是研究OGA在健康和疾病中的作用的有用工具。
Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.