Rapid synthesis of complex bioactive alkaloids

许多重要的药物都是天然产物，或者是从天然产物中衍生出来的，或者是受天然产物的启发而产生的。例如许多抗生素，如β -内酰胺类，止痛药，如吗啡，以及抗癌剂，如紫杉醇，紫杉醇最初是从太平洋紫杉树中提取的。尽管这些天然产物有着良好的记录，但它们的分子复杂性可能成为研发工作的严重障碍，因为这些化合物几乎无法从自然界获得，而且难以操作。与此同时，越来越需要新的原料药来对付未解决的疾病状态，特别是癌症，并对付耐药性的出现。越来越多的人认为，制药行业在考虑潜在药物支架的种类时需要更加冒险，而且分子的复杂性，包括手性，可以带来更好的选择性。研究更多的天然产物基序可能是高利润的，并产生重要的新药。我们的项目旨在发明获得天然产物生物碱结构的特定家族及其近亲的新途径。这些基于桥接环二肽核心结构的化合物是非常有吸引力的候选者，因为简单的变体已经被用作药物-即它们是“可药物的”。我们的目标是制造更复杂的化合物，但作为药物具有显着的潜力，因为这类化合物的特定成员是有效的抗肿瘤剂，或者具有在这方面有用的酶抑制活性（例如钙调素抑制活性），或者具有抗寄生虫活性。这些化合物可以成为重要的药物，既可以提高人类医学水平，也可以对英国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小组做出了努力，但合成这些化合物的最佳途径通常是20多个合成步骤——太长，效率太低，对工业没有吸引力。相比之下，我们打算在几个合成步骤中制造这些类型的化合物，通过使用级联过程，在一个步骤中形成多个键。我们已经确定了我们的想法背后的基本原则，现在正在寻求资金，以探索新战略的范围和目标应用。为了通过这种化学反应获得不同的结构，提出了额外的新概念层，并且还提出了级联反应的新变体，使用自由基中间体代替阳离子。

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.