Abstract：
Sugar phosphates are emerging as potential therapeutic candidates for certain diseases. However, their high polarity makes them poorly absorbed by the body and their penetration inside the cell is even more difficult without a proper transporter. Amino sugar phosphates (n-amino-n-deoxy-sugars, carbohydrates in which a hydroxyl group has been replaced with an amine group), such as N-acetyl-D-mannosamine (ManNac)-6-phosphate have shown potential as a treatment for a muscular disease called GNE myopathy caused by a deficiency in the production of sialic acid. However, its high polarity leads to poor absorption and consequent high dosage in humans, causing unwanted side effects. Herein, we describe the application of phosphoramidate prodrug chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG), caused by mutations in the gene \"GNE,\" that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Synthesis of 2-Acetamido-1,3,4-tri-O-acetyl-2-deoxy-D-mannopyranose. Basic Protocol 2: Preparation of 3-acetamido-6-((((((S)-1-ethoxy-4-methyl-1-oxo-pentan-2-yl) amino) (phenoxy)phosphoryl) oxy) methyl) tetrahydro-2H-pyran-2,4,5-triyl triacetate (5). Support Protocol: Preparation of ethyl (chloro(phenoxy)phosphoryl)-l-leucinate.
摘要：
糖磷酸盐正在成为某些疾病的潜在治疗候选物。然而,它们的高极性使它们很难被身体吸收，如果没有适当的转运蛋白，它们在细胞内的渗透就更加困难。氨基糖磷酸盐（n-氨基-n-脱氧糖，其中羟基已被胺基取代的碳水化合物)，例如N-乙酰-D-甘露糖胺(ManNac)-6-磷酸已显示出作为治疗由唾液酸产生缺乏引起的称为GNE肌病的肌肉疾病的潜力。然而,它的高极性导致人体吸收不良和随之而来的高剂量，造成不必要的副作用。在这里，我们描述了氨基磷酸酯前药化学对1,3,4-O-乙酰化N-乙酰甘露糖胺（Ac3ManNAc）的应用，以提供ManNAc-6-磷酸（ManNAc-6-P），唾液酸生物合成的关键中间体。唾液酸缺乏是GNE肌病的标志，一种罕见的先天性糖基化疾病（CDG），由基因\“GNE”的突变引起的，\“这限制了ManNAc-6-P的生产。开发了合成方法以提供Ac3ManNAc-6-氨基磷酸酯的文库,在一系列研究中评估了其作为GNE肌病治疗的潜力。©2022作者WileyPeriodicalsLLC出版的当前协议。基本方案1:2-乙酰氨基-1,3,4-三-O-乙酰基-2-脱氧-D-吡喃甘露糖的合成。基本方案2:制备3-乙酰氨基-6-((((S)-1-乙氧基-4-甲基-1-氧代-戊-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)四氢-2H-吡喃-2,4,5-三乙酸酯(5)。支持方案:制备(氯(苯氧基)磷酰基)-1-亮氨酸乙酯。
