Under water control: A cascade approach to the pseudolaric acid anti-tumour agents

在与疾病的持续斗争中，我们在设计新疗法时向大自然寻求灵感。具有生物活性的天然分子通常具有独特的复杂分子结构，这些分子结构已经进化了数千年，可以选择性地与生物系统相互作用。我们称这些天然存在的分子为“天然产物”。伴随着这些奇妙复杂的结构而来的是一个重大的科学挑战：如果我们不能从自然中分离出我们需要的东西，就像通常情况下那样，我们能在实验室中从头开始有效地合成这些物质吗？在这个项目中，我们将开发新的反应，使我们能够非常快速有效地构建称为土槿皮酸的天然产物。土槿皮酸具有挑战性的结构，并有可能激发突破性的抗肿瘤药物。该家族的一个成员土槿皮酸B已被证明可以避免许多抗肿瘤药物所遭受的耐药性问题，因此该天然产物对多药耐药性癌症具有活性。例如，土槿乙酸B已被证明对肝癌具有活性，该肝癌对著名的抗癌剂紫杉醇的治疗具有抗性。我们对土槿乙酸的方法将涉及新的“级联”反应，该反应允许简单的起始材料在一个反应烧瓶中级联成复杂的分子，仅使用一种试剂。级联反应具有很大的经济意义，因为它们从化学反应中提取高价值，节省步骤，从而节省时间，化学资源，并最大限度地减少废物的产生。我们将开发的级联也将使我们能够控制正在构建的分子的形状或立体化学。级联反应将通过向起始材料提供电子来触发。反应瓶中存在的水将促进电子转移过程，因此我们说反应是“在水控制下”的。我们迫切需要并热切寻求改进分子构建方式。我们的研究产生的新的选择性化学反应将使化学家在未来构建分子时简化路线，从而节省宝贵的资源。我们实验室在发现由电子转移介导的新有机反应方面的初步结果意味着我们处于独特的位置来迎接这一挑战。获得具有重要生物学意义的天然产物土槿乙酸B的类似物是一个重要而及时的问题。尽管土槿皮酸B已被证明与微管蛋白上的新位点结合并对多药耐药癌症具有活性，但该分子的结构与其抗肿瘤活性之间的联系尚不清楚。我们对土槿乙酸分子骨架的简明方法将使我们能够改变结构，从而制备与土槿乙酸相关的“非天然产物”。这些类似物的生物学测试将使我们对分子如何发挥其重要的生物学作用有一个独特的了解。最终，我们的研究可能会导致新的药物和生活质量的改善，在世界范围内。

In the constant battle against disease, we look to nature for inspiration in the design of new therapeutics. Biologically-active, naturally-occuring molecules often have unique, complex molecular architectures that have evolved over millennia to interact selectively with biological systems. We call these naturally-occuring molecules 'natural products'. With these wonderfully intricate structures comes a major scientific challenge: if we can't isolate what we need from nature, as is often the case, can we synthesise these substances efficiently from scratch in the laboratory?In this project, we will develop new reactions that will allow us to build natural products called the pseudolaric acids very quickly and efficiently. The pseudolaric acids have challenging structures and the potential to inspire ground-breaking, anti-tumour drugs. One member of this family, pseudolaric acid B, has been shown to circumvent the problems of resistance from which many anti-tumour drugs suffer, thus the natural product is active against multi-drug resistant cancers. For example, pseudolaric acid B has been shown to be active against a liver cancer that is resistant to treatment by the famous anti-cancer agent Taxol.Our approach to the pseudolaric acids will involve new 'cascade' reactions that allow simple starting materials to cascade through to complex molecules in just one reaction flask, using just one reagent. Cascade reactions make great economic sense as they extract high value from a chemical reaction, saving steps and therefore time, chemical resources, and minimising waste generation. The cascades that we will develop will also allow us to control the shape, or stereochemistry, of the molecule under construction. The cascade reactions will be triggered by supplying electrons to the starting materials. The electron-transfer processes will be facilitated by the water present in the reaction flask thus we say the reactions are 'under water control'.Improvements in the way we build molecules are urgently needed and are eagerly sought. The new, selective chemical reactions that result from our studies will allow chemists to streamline routes when building molecules in the future, thus saving precious resources. The preliminary results from our laboratory on the discovery of new organic reactions mediated by electron-transfer means that we are uniquely placed to meet this challenge. Obtaining analogues of the biologically-important natural product pseudolaric acid B is a significant and timely problem. While pseudolaric acid B has been shown to bind to a new site on tubulin and to be active against multi-drug resistant cancers, the link between the structure of the molecule and its anti-tumour activity is not understood. Our concise approach to the molecular skeleton of the pseudolaric acids will allow us to make changes to the structure and thus to prepare 'unnatural products' related to the pseudolaric acids. The biological testing of these analogues will give us a unique insight into how the molecule exerts its important biological effect. Ultimately, our studies may lead to new drugs and to improvements in the quality of life, worldwide.