A chemoselective ligation route to glycosyltransferase substrate mimetics

要想在治疗感染和疾病方面取得新的进展，详细了解细胞的先天工作是必不可少的。我们身体的细胞如何应对从癌症到普通感冒的各种压力，都是人们高度追求的知识。为了帮助揭示这些信息，我们打算设计一系列可以进入细胞并关闭特定蛋白质功能的小化合物，以观察对细胞的影响并揭示特定蛋白质在细胞维护中的作用。这可以通过使用模仿蛋白质正常工作的化学物质来实现，并利用它们来分散蛋白质的正常工作。我们想模拟糖核苷酸（sugar- ndp）。糖- ndp是一类细胞内生物催化蛋白（称为糖基转移酶（GTs））所使用的构建块。GTs生物合成低聚糖和糖蛋白，它们是细胞功能和维持的核心参与者。糖- ndp携带一些“排斥脂肪”的负电荷，阻止它们通过油腻的细胞膜逃离细胞的水分内部，但也阻止糖- ndp模拟物进入细胞。制备不带电的糖- ndp模拟物的能力是非常理想的，这种模拟物最终可以扩散到细胞中并扰乱特定gt的功能。我们将开发合成化学方法，通过取代带负电荷的糖- ndp（即ndp）成分来促进糖- ndp样化合物的制备。焦磷酸基团)和糖分子。糖应该能够模拟缺失的焦磷酸盐成分，也有助于使糖- ndp模拟物更油腻。这将增加它进入细胞的机会穿过油腻的细胞膜来完成手头的工作。目前合成这类分子的方法尤其具有挑战性和耗时。然而，我们将设计一系列简单的化学构建模块，将它们以不同的组合方式“剪切”在一起，这样就有可能以较低的劳动密集型方式制备一系列不带电的糖- ndp样结构。

A detailed understanding of the innate workings of the cell is imperative for our prospects of making new advances in the treatment of infections and disease. How the cells of our body respond to stresses ranging from cancer to the common cold is all highly sought knowledge. To help reveal this information we intend to design a range of small chemical compounds which can get into the cells and shut down the function(s) of specific proteins in order to observe the effects on the cell and reveal the role of specific proteins in cell maintenance. This can be achieved by using chemicals which mimic the ones the proteins normally work with and use them to distract the protein from doing its proper job. We want to mimic sugar nucleotides (sugar-NDPs).Sugar-NDPs are the building blocks used by a class of intracellular biocatalytic proteins know as glycosyltransferases (GTs). GTs biosynthesise oligosaccharides and glycoproteins which are central players in cellular function and maintenance. Sugar-NDPs carry some 'fat-repelling' negative charge which stops them from escaping the cells' watery innards through the greasy cell membrane, but also prevents the delivery of sugar-NDP mimics into the cell. The ability to prepare uncharged sugar-NDP mimetics which can ultimately diffuse into cells and perturb the function of specific GTs would be extremely desirable. We will develop synthetic chemical methods that will facilitate the preparation of such sugar-NDP-like compounds by replacing the negatively charged component of the sugar-NDP (ie. the pyrophosphate group) with a sugar molecule. The sugar should be able to mimic the missing pyrophosphate component and also help to make the sugar-NDP mimic more greasy. This will increase its chances of getting into get into the cell across the greasy cell membrane to do the job at hand. Current methods for synthesising such molecules can be particularly challenging and time consuming. However we will design a selection of simple chemical building blocks that be chemically 'clipped' together in different combinations so that it will be possible to prepare a range of uncharged sugar-NDP-like structures in a less labour intensive manner.