权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Diversity Oriented Synthesis of Farnesyl Pyrophosphate Analogues as Mechanistic Probes and as Precursors to Modified Natural Products

作为机制探针和改性天然产物前体的法呢基焦磷酸类似物的多样性导向合成

基本信息

批准号：
EP/D069580/1
负责人：
Rudolf Allemann
金额：
$ 40.58万
依托单位：
CARDIFF UNIVERSITY
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FD069580%2F1
关键词：
Diversity Oriented Synthesis Farnesyl Pyrophosphate

项目摘要

Sesquiterpenes are an important class of natural products that exhibit a wide variety of structural variation and biological function with applications ranging from uses as scents and oils to agrochemicals and pharmaceuticals. In contrast to this diversity they are, however, metabolites originating from a single parent compound, farnesyl pyrophospate (FPP). This incredible array of products is generated from FPP by a single class of enzyme, sesquiterpene cyclases, all of which share a common 3D structure. To understand how this stunning diversity of products is formed from one compound with such remarkable fidelity is a major challenge for modern chemical biology. Each sesquiterpene cyclase enzyme must guide neutral or carbocationic intermediates through a series of specific steps whilst preventing reaction with solvent and rearrangement to undesired by-products of very similar energy and conformation.In order to examine and solve this problem we intend to synthesise a series of FPP analogue compounds and challenge sesquiterpene cyclase enzymes with them. The synthesis of these compounds is designed in such a way that a combinatorial approach may be used in the future in order to prepare diverse libraries of these materials. In this study the compounds are designed to test the proposed mechanisms by which sesquiterpene cyclases guide FPP and intermediate materials to the sesquiterpene products. The proposed compounds bear functional groups that are designed to either stabilise or destabilise carbocationic intermediates that have been predicted to form during the formation of sesquiterpene hydrocarbons. They should therefore give predictable products when tested with our range of sesquiterpene cyclase enzymes if the proposed mechanisms of action are true. If this does not prove to be the case then they will give us information allowing us to propose mechanisms that fit all the observed experimental data. FPP analogues that prove to be substrates for these enzymes will inevitably produce sesquiterpenoid materials of novel structure and function. This will expand the range of biologically active compounds that are available to us and moreover, these compounds, which often have complex structures will have been prepared without tedious and expensive total synthesis.

倍半萜是一类重要的天然产物，具有广泛的结构变化和生物学功能，用途广泛，从香料、油脂到农用化学品和医药。然而，与这种多样性相反的是，它们是源自单一母体化合物焦磷酸法尼酯(FPP)的代谢物。这一系列令人难以置信的产品是由FPP由单一类别的酶-倍半萜环酶产生的，所有这些酶都共享一个共同的3D结构。要了解这种令人惊叹的多样化产品是如何由一种具有如此惊人保真度的化合物形成的，这是现代化学生物学面临的主要挑战。每个倍半萜环化酶必须引导中性或碳阳离子中间体通过一系列特定的步骤，同时防止与溶剂反应和重排产生能量和构象非常相似的不良副产物。为了检测和解决这个问题，我们打算合成一系列FPP类似物，并用它们来挑战倍半萜环化酶。这些化合物的合成是以这样一种方式设计的，即未来可以使用组合方法来准备这些材料的不同库。在这项研究中，化合物的设计是为了测试倍半萜环化酶引导FPP和中间体生成倍半萜产物的机制。所建议的化合物含有旨在稳定或破坏碳阳离子中间体的官能团，这些中间体已被预测在倍半萜碳氢化合物的形成过程中形成。因此，如果所提出的作用机制属实，当用我们的倍半萜环酶范围进行测试时，它们应该提供可预测的产品。如果事实证明并非如此，那么他们将给我们提供信息，让我们提出符合所有观察到的实验数据的机制。作为这些酶的底物的FPP类似物将不可避免地产生结构和功能新颖的倍半萜类物质。这将扩大我们可用的生物活性化合物的范围，而且，这些通常具有复杂结构的化合物将在没有繁琐和昂贵的全合成的情况下被制备出来。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Crystal structure of (+)-delta-cadinene synthase from Gossypium arboreum and evolutionary divergence of metal binding motifs for catalysis.

DOI：
10.1021/bi900483b
发表时间：
2009-07-07
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Gennadios, Heather A.;Gonzalez, Veronica;Di Costanzo, Luigi;Li, Amang;Yu, Fanglei;Miller, David J.;Allemann, Rudolf K.;Christianson, David W.
通讯作者：
Christianson, David W.

Mechanistic insights from the binding of substrate and carbocation intermediate analogues to aristolochene synthase.

DOI：
10.1021/bi400691v
发表时间：
2013-08-13
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Chen, Mengbin;Al-lami, Naeemah;Janvier, Marine;D'Antonio, Edward L.;Faraldos, Juan A.;Cane, David E.;Allemann, Rudolf K.;Christianson, David W.
通讯作者：
Christianson, David W.