Synthesis of activated 6-deoxy-6-fluorosugars: biomimetic feedstocks for combinatorial biosynthesis

在自然界中，有价值的抗生素分子是由糖元成分（通常是一个大的复杂环状分子）与一个或多个修饰的糖分子糖基化而生物合成的。这种糖基化事件对活性至关重要，也是新型抗生素的潜在来源，可以显示出更好的性能，最重要的是治疗越来越成问题的多重耐药细菌菌株。由于它们的复杂性，化学合成这些潜在的新试剂非常具有挑战性；然而，如果自然界的机制可以用来向苷元中添加非天然糖，我们就可以更容易地发现新的药物。这种活性需要合成非天然糖，将其激活为适合糖基转移酶（GT）处理的NDP糖，并将其转移到苷元上。我们提出的方案结合了所有这些因素。非天然糖的制备采用化学合成方法，而对其进行活化则采用化学酶法和酶法。然后，我们将探索使用一系列商业的、专有的和研究用的gt将非天然糖转化为苷元。使用氟糖是因为它们在自然界中是未知的，并且期望赋予糖基化分子有用的特性。

In Nature, valuable classes of antibiotic molecules are biosynthesised from an aglycone component (usually a large complex cyclic molecule) which is glycosylated with one or more modified sugar molecules. This glycosylation event is essential for activity, and is also a potential source of the novel antibiotics which could show improved properties, most importantly for the treatment of multidrug-resistant bacterial strains which are becoming increasingly problematic.Because of their complexity, chemical synthesis of these potential new agents is very challenging; however, if the machinery of nature can be used to add unnatural sugars to aglycones, we could discover novel agents considerably more easily. This activity requires the synthesis of the unnatural sugars, their activation to NDP sugars suitable for processing by a glycosyl transferase (GT) enzyme and their transfer to the aglycone. Our proposed programme combines all these elements. Chemical synthesis is used to prepare the unnatural sugars, while chemoenzymatic and enzymatic methods will be used to activate them. We will then explore the use of a range of commercial, proprietary and research GTs to transfer unnatural sugars to aglycones. Fluorosugars are used because they are unknown in nature and are expected to confer useful properties on the glycosylatedmolecules.