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Total synthesis of the guanacastepenes

胍那卡斯特烯的全合成

基本信息

批准号：
EP/E033261/1
负责人：
Michael Greaney
金额：
$ 15.2万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FE033261%2F1
关键词：
Total synthesis guanacastepenes

项目摘要

Molecules come in all shapes and sizes, and new ways of making them are central to just about every industry in the twenty-first century. Medicine, manufacturing, cosmetics and agriculture are just a few important examples of industries that depend on chemists coming up with new molecules and new methods for putting them together. The current proposal is looking to make one of nature's molecules, called guanacastepene, a natural product that is found in tropical mushrooms. The construction of a natural product by chemists in a laboratory is a challenging endeavour, as the structure of these molecules is often very complex. As a result, chemistry of the highest quality is needed. We are trying to invent new chemical reactions that are designed to be especially powerful for making complicated structures like natural products. The use of nature's molecules to inspire bigger and better chemistry is a hallmark of this branch of science; many of the chemical reactions now taken for granted and used all over the world arose from research programmes in natural product chemistry. Just as the synthesis of natural products have inspired advances in the chemical sciences, they are responsible for huge innovations in biology and medicine. The use of plants and herbs as natural remedies has been documented since the beginning of recorded history. What is arguably less well-known is that this process continues to this day within the laboratories of the pharmaceutical industry. Estimates have put the percentage of modern medicines that derive from natural products as high as 50%. The natural products can be used directly, such as aspirin or penicillin; modified slightly by chemists to produce medicines (e.g. the cholesterol lowering drug Mevacor) or modified more substantially such that the natural product represents a kind of starting point. In the current proposal, the natural product guanacastepene has powerful biological activity against the virulent pathogen MRSA, the number one target for the development of new antibacterial drugs. However, it is far too toxic to stand as a drug in its own right, and falls into the category alluded to above as one of nature's molecules that needs to be chemically modified before its potential as a medicine can be harnessed. In synthesising this molecule in the laboratory, we aim to develop the chemistry necessary for modification of guanacastepene such that it loses its toxicity but retains its antibacterial activity, opening the door to explore its potential as a new drug for the treatment of infection.

分子有各种形状和大小，制造它们的新方法对21世纪几乎每个行业都至关重要。医药、制造业、化妆品和农业只是依赖化学家提出新分子和将它们组合在一起的新方法的行业的几个重要例子。目前的提议是寻找一种叫做guanacastepene的天然分子，这是一种在热带蘑菇中发现的天然产物。化学家在实验室中构建天然产物是一项具有挑战性的工作，因为这些分子的结构通常非常复杂。因此，需要最高质量的化学反应。我们正在努力发明新的化学反应，这些化学反应被设计得特别强大，可以制造出像天然产品这样的复杂结构。利用自然分子激发更大更好的化学反应是这一科学分支的一个标志；许多现在被认为理所当然并在全世界使用的化学反应都起源于天然产物化学的研究项目。正如天然产物的合成激发了化学科学的进步一样，它们也推动了生物学和医学的巨大创新。自从有历史记载以来，植物和草药作为自然疗法的使用就有了记载。鲜为人知的是，这个过程在制药工业的实验室里一直持续到今天。据估计，源自天然产物的现代药物比例高达50%。天然产物可直接使用，如阿司匹林或青霉素；经过化学家的轻微修改以生产药物（例如降胆固醇药物美卫可），或者经过更大幅度的修改，使天然产物成为一种起点。在目前的提案中，天然产物guanacastepene对MRSA具有强大的生物活性，是开发新型抗菌药物的首要目标。然而，它本身的毒性太大，不能作为一种药物，它属于上面提到的一种自然分子，需要经过化学修饰才能成为一种药物。在实验室合成这种分子的过程中，我们的目标是开发对胍纳卡斯丁烯进行修饰所需的化学物质，使其失去毒性，但保留其抗菌活性，为探索其作为治疗感染的新药的潜力打开大门。