Holicek Viktor, Deen Matthew, Bhosale Sandeep, Ashmus Roger A, Vocadlo David J
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5S 1P6, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5S 1P6, Canada.
ACS Omega. 2024 Dec 8;9(50):49223-49228. doi: 10.1021/acsomega.4c06141. eCollection 2024 Dec 17.
Altered levels of intracellular protein glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) have emerged as being involved in various cancers and neurodegenerative diseases. OGA inhibitors have proven critically useful as tools to help understand the roles of O-GlcNAc, yet accessing large quantities of inhibitors necessary for many animal studies remains a challenge. Herein is described a scalable method to produce Thiamet-G, a potent, selective, and widely used brain-permeable OGA inhibitor. This synthetic route begins with inexpensive precursor, requires no column chromatography, employs simple nontoxic reagents, and in a single campaign can furnish several hundred grams of crystalline Thiamet-G in an overall yield of 44% over six steps.
细胞内蛋白质O-连接β-N-乙酰葡糖胺（O-GlcNAc）糖基化水平的改变已被证明与多种癌症和神经退行性疾病有关。OGA抑制剂已被证明是帮助理解O-GlcNAc作用的关键工具，但要获得许多动物研究所需的大量抑制剂仍然是一个挑战。本文描述了一种可扩展的方法来生产噻美特-G，一种有效、选择性且广泛使用的可透过血脑屏障的OGA抑制剂。该合成路线起始于廉价的前体，无需柱色谱，使用简单无毒的试剂，并且在一个批次中可以通过六个步骤以44%的总收率提供几百克结晶噻美特-G。
