Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
Department of Chemistry, University of York, York (UK).
Angew Chem Int Ed Engl. 2015 Dec 14;54(51):15429-33. doi: 10.1002/anie.201507985. Epub 2015 Nov 6.
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.
基于吡咯烷的亚氨基环糖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差向异构化策略，可直接获得一系列立体异构的 O-连接的 N-乙酰氨基葡萄糖（O-GlcNAc）水解酶（OGA）抑制剂。这些抑制剂与细菌同源 OGA 的结合结构细节揭示了其效力的基础。这些化合物可口服，并渗透到啮齿动物的大脑中以增加 O-GlcNAc，它们应该是研究 OGA 在健康和疾病中的作用的有用工具。
