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Rapid synthesis of complex bioactive alkaloids

复杂生物活性生物碱的快速合成

基本信息

批准号：
EP/H013040/1
负责人：
Nigel Simpkins
金额：
$ 38.5万
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FH013040%2F1
关键词：
Rapid synthesis complex bioactive alkaloids

项目摘要

Many important pharmaceuticals are natural products or are derived from, or inspired by, natural products. Examples include many antibiotics, such as beta-lactams, painkillers, such as morphine,and anti-cancer agents, like taxol, which was orginally produced from the Pacific Yew tree. Although such natural products have a great track record, their molecular complexitycan prove a serious obstacle to R&D efforts, since the compounds can be scarcely available from Nature, and difficult to manipulate. At the same time, there is an increasing need for new drug substances to combat unsolved disease states, particularly cancers, and to combat the onset of drug resistance. There is a growingacceptance that the pharma industry needs to be more adventurous in the kinds of potential drug scaffolds that it considers, and also that molecular complexity, includingchirality, can lead to better selectivity. Investigating greater numbers of natural product motifs could be highly profitable, and yield important new drugs. Our project is aimed at inventing new routes to obtain particular families of natural product alkaloid structures, and their close relatives. These compounds, based on a bridged cyclic dipeptide core structure are very attractive cadidates, since simple variants have already been adopted as pharmaceuticals - i.e. they are ''drug-able''. The compounds that we aim to make are much more complex, but show remarkable potential as medicinal agents, since specific members of this class are potent antitumour agents, or have enzyme inhibitory activity that could be useful in this regard (e.g. calmodulin inhibitory activity), or haveanti-parasitic activity. Such compounds could become important drugs, which would both enhance human medicine and impact upon the UK pharma economic base.However, up until now, these compounds have only been available through rather long synthesis routes. Despite the efforts of three of the best known synthesis groupsin the US, the best routes to these compounds are usually well over 20 synthesis steps - too long and inefficient to be attractive to industry. In contrast, we intend to make these types of compound in only a handfull of synthetic steps, by using cascade processes in which multiple bonds are formed in one step.We have established the basic principle behind our idea, and are now seeking funds to explore the scope and target applications of the new strategy. Additional layers ofnew concepts are proposed in order to access diverse structures via this chemistry, and novel variants of the cascade reactions are also proposed, using radical intermediates in placeof cations.

许多重要的药品都是天然产品，或者是从天然产品中提取出来的，或者是受天然产品启发的。例子包括许多抗生素，如β-内酰胺类，止痛药，如吗啡，以及抗癌药物，如紫杉醇，它是从太平洋红豆杉中有机生产出来的。虽然这类天然产物有很好的记录，但它们的分子复杂性可能会被证明是研发工作的严重障碍，因为这些化合物几乎不能从大自然中获得，而且很难操纵。与此同时，人们越来越需要新的药物物质来对抗未解决的疾病状态，特别是癌症，并对抗耐药性的出现。越来越多的人接受，制药业需要在其考虑的潜在药物支架类型上更具冒险精神，而且包括手性在内的分子复杂性可以带来更好的选择性。研究更多的天然产物基序可能是非常有利可图的，并产生重要的新药。我们的项目旨在发明新的途径来获得特定的天然产物生物碱结构家族及其近亲。这些基于桥联环二肽核心结构的化合物是非常有吸引力的化合物，因为简单的变体已经被用作药物--也就是说，它们是“可用药的”。我们的目标是制造复杂得多的化合物，但显示出作为药物的巨大潜力，因为这类特定成员是有效的抗肿瘤药物，或具有在这方面有用的酶抑制活性(例如，钙调素抑制活性)，或具有抗寄生虫活性。这些化合物可能会成为重要的药物，既可以提高人类的医学水平，也可以对英国的制药经济基础产生影响。然而，到目前为止，这些化合物只能通过相当长的合成路线才能获得。尽管美国三个最著名的合成集团做出了努力，但获得这些化合物的最佳路线通常超过20个合成步骤-太长且效率低下，对工业没有吸引力。相比之下，我们打算通过一步形成多个键的级联过程，在几个合成步骤中合成这些类型的化合物。我们已经确立了我们想法背后的基本原则，目前正在寻求资金，以探索新战略的范围和目标应用。为了通过这种化学获得不同的结构，提出了额外的新概念层，还提出了级联反应的新变体，使用自由基中间体取代阳离子。