Waiting in line: A sequenced approach to the antibacterial pleuromutilin

对抗生素的耐药性是全世界关注的一个主要问题，并导致迫切需要鉴定具有不同于既定类别的作用模式的抗生素和抗菌剂。抗菌天然产物截短侧耳素就是这样的候选者。截短侧耳素是已知的目标'蛋白质工厂'或核糖体在细菌中，阻止他们使他们需要生存的分子。不幸的是，截短侧耳素有一个复杂的三维结构，很难合成。另一个问题是截短侧耳素的“药代动力学”特性较差。药代动力学是研究人体对药物的反应。在截短侧耳素的情况下，该化合物容易被生物系统中的酶代谢。虽然天然产物本身不是一种很好的药物，截短侧耳素的类似物看起来很有前途，但当结构如此具有挑战性时，我们如何制备天然产物的类似物？一个解决方案是开发一种从头开始构建截短侧耳素的方法。在这个项目中，我们将开发化学，使我们能够做到这一点。为了保持合成短，我们建议开发一种新的化学方法，将构建截短侧耳素的骨架在一个反应。为此，我们将使用镧系元素试剂SmI2来协调化学“序列”，以便我们获得高产率，同时实现对产物形状或“立体化学”的良好控制。我们的研究将产生强大的有机反应，供其他化学家使用，并将提高我们对反应工作方式的理解。我们的截短侧耳素路线将允许获得否则不可能制备的类似物。这些类似物可能会成为未来的药物。

Resistance to antibiotics is a major concern worldwide and has led to an urgent need to identify antibiotics and antibacterials with modes of action distinct from the established classes. The antibacterial natural product pleuromutilin is such a candidate. Pleuromutilin is known to target the 'protein factories' or ribosomes in bacteria, stopping them making the molecules they need to survive.Unfortunately, pleuromutilin has a complex 3D structure and is difficult to synthesise. The other problem is that pleuromutilin has poor 'pharmacokinetic' properties. Pharmacokinetics is the study of what the body does to a drug. In the case of pleuromutilin, the compound is readily metabolised by enzymes in biological systems. Although the natural product itself is not a very good drug, analogues of pleuromutilin look promising, but how can we prepare analogues of the natural product when the structure is so challenging?One solution is to develop a way of building pleuromutilin from scratch. In this project, we will develop chemistry that allows us to do this. To keep the synthesis short, we propose to develop a new chemical process that will construct the skeleton of pleuromutilin in one reaction. To do this we will use the lanthanide reagent SmI2 to orchestrate the chemical 'sequence' so that we get a high yield while achieving good control over the shape or 'stereochemistry' of the product. Our research will produce powerful organic reactions for other chemists to use and will improve our understanding of the way reactions work. Our route to pleuromutilin will allow access to analogues that would otherwise be impossible to prepare. These analogues could go on to to become future drugs.