Organic Catalysts Incorporating Catalytic Triads

几乎每天都能在自然生物和人造化合物中发现具有潜在有用生物活性的新化合物/无论是对癌细胞的毒性还是抗生素特性。随后，经常检查密切相关的结构，以确定这些分子的哪些部分负责有益作用。在这种药物开发过程中，可能会合成数千种分子，以追求一种具有理想的医疗效果，易于被人体吸收并且无毒的分子。因此，合成化学在每一个阶段都具有根本的重要性。与此同时，生物科学的许多最新进展（如人类基因组序列的完成）提高了确定新疾病治疗潜在目标的速度。因此，针对这些新目标的药物分子的需求正在迅速增加，而高效、有效的化学合成方法，特别是那些导致构建药物共同结构特征的方法，是至关重要的。拟议的研究侧重于开发用于化学合成的新“催化”方法，其中只需要少量的化学试剂（“催化剂”）就可以将大量的起始材料转化为产品。催化剂的设计将受到天然酶的启发，这种酶能够以催化的方式进行无数的化学反应。我们还将从现有的化学方法中获得灵感，以进行正在研究的反应，并将其用于催化方式。我们将集中讨论的化学反应在最近的一些文件（由全球制药业、美国化学学会和英国政府研究委员会的代表发表）中被确定为在药物分子合成中具有根本重要性。这些文件指出，目前缺乏进行这些过程的有效和环境友好的化学方法，迫切需要针对开发这种方法进行学术研究。例如，酰胺键存在于超过25%的现有药物分子中，也存在于蛋白质等自然存在的分子中，它们的形成是有机化学中最常见的转化之一。然而，目前还没有有效的催化方法来形成这些键。事实上，现有的非催化技术往往需要大量昂贵和/或有毒的化学试剂。我们将致力于开发简单的有机（碳基）分子作为这种反应的催化剂，这种催化剂将通过“抓住”和“组织”起始材料，并指导它们一起反应形成酰胺键。这种新工艺的唯一化学副产品将是水和少量的催化剂本身，可以回收和循环利用。这种催化剂将在许多科学研究途径中具有直接和深远的应用。这项工作中概述的概念也将应用于许多其他重要化学反应的催化剂的开发。这些新型催化剂将广泛应用于分子合成，用作新药和农用化学品，以及活细胞过程的研究，因此对化学、医学和生物学许多领域的科学家都是有益的。

New chemical compounds which exhibit potentially useful biological activity / be it toxicity against cancer cells or antibiotic properties, are identified on an almost daily basis in both natural organisms and collections of man-made compounds. Subsequently, closely related structures are often examined to determine which parts of these molecules are responsible for the beneficial effects. In the course of this drug development process, thousands of molecules may be synthesized in pursuit of just one that has the desirable medical effects, is readily absorbed by the body and is non-toxic. Synthetic chemistry is therefore of fundamental importance at every stage. Meanwhile, the many recent advances in the biological sciences (such as the completion of the human genome sequence) have increased the rate at which potential targets for new disease treatments can be identified. As a consequence, the demand for drug molecules directed towards these new targets is increasing rapidly, and efficient, effective methods of chemical synthesis, particularly those which result in the construction of structural features common in drugs, are of paramount importance.The proposed research focuses on the development of new 'catalytic' methods for chemical synthesis, in which only a small quantity of chemical reagent (a 'catalyst') is required in order to convert much larger quantities of starting materials into products. The catalyst design will be inspired by natural enzymes, which are able to carry out countless chemical reactions in a catalytic fashion. We will also take inspiration from existing chemical methods for carrying out the reactions under investigation, adapting them for use in a catalytic manner. The chemical reactions which we will concentrate on have been identified in a number of recent documents (published by representatives of the global pharmaceutical industry, the American Chemical Society and the UK government research councils) as being of fundamental importance in the synthesis of drug molecules. These documents noted that there is currently a lack of efficient and environmentally-friendly chemical methods for carrying out these processes and that academic research directed towards developing such methods is urgently required.For example, amide bonds are found in more than 25% of existing drug molecules, as well as in naturally occurring molecules such as proteins, and their formation is amongst the most common of all transformations in organic chemistry. There are, however, currently no effective catalytic methods for forming these bonds. Indeed, the existing, non-catalytic technologies often require large quantities of chemical reagents that are expensive and/or toxic. We will aim to develop simple organic (carbon-based) molecules as catalysts for this reaction which will act by 'holding onto' and 'organising' the starting materials, and directing them to react together to form the amide bond. The only chemical by-products of this new process will be water and the small quantity of the catalyst itself, which can be recovered and recycled. Such a catalyst would have immediate and far-reaching application in many avenues of scientific research. The concepts outlined in this work will also be applied to the development of catalysts for many other important chemical reactions.These new catalysts will have widespread application in the synthesis of molecules for use as new drugs and agrochemicals and in the study of living cell processes, and as such will be beneficial to scientists working in many areas of chemistry, medicine and biology.