Novel strategies to access chiral heterocycles as potential lead compounds in drug discovery

新药的开发（药物发现）对于改善世界人口的健康至关重要。解决当前的医疗需求需要以新的方式发挥作用的药物。因此，正在研究更复杂的生物相互作用作为目标。然而，寻找药物开发的良好起点，将针对这些复杂的生物靶点，提出了一个艰巨的挑战。历史上，药物开发的起点，被称为先导化合物，来自天然的小分子结合的目标。然而，这些通常不可用，特别是在复杂的结合相互作用中。制药工业中化合物集合的筛选在寻找更复杂靶标的先导化合物方面也基本上不成功。这是因为工业化合物集合通常聚集在相对较少的结构类型周围，并且经常依赖于平面（非手性）结构。需要替代方法来产生可用作药物先导物的更多样化和3维（手性）分子。事实上，制药行业目前对关注更少，更高质量的先导化合物感兴趣。这项研究将开发新的化学方法，以合成具有药物发现先导化合物潜力的各种分子框架。这些框架将围绕手性（3-D）杂环。杂环是在环中含有至少一个杂原子（即氧、氮或硫原子）的碳基环结构，并且通常是药物化合物的必需组分。特别是手性杂环化合物为高质量的先导化合物提供了理想的性质，它们体积小，具有理想的物理性质，并且具有确定的三维形状，这对于与生物系统的结构和结合相互作用至关重要。从简单，易得的起始材料合成这些复杂的杂环分子具有根本的兴趣和主要的合成挑战。该提案的关键合成创新是为实现这一目标而发明、开发和应用新的化学试剂。这些试剂含有多种功能，在合成中发挥多种作用很重要。本论文将发展三种手性杂环化合物的合成方法，并控制其三维形状。此外，这些合成方法将允许将各种化学基团直接引入到分子的杂环核上。这将使人们能够快速获得目前在工业化合物集合中没有很好代表的各种分子框架。由这些新方法产生的化合物作为针对各种生物靶标的潜在先导化合物是令人感兴趣的。为了证明这一点，将制备一系列类似物，这些类似物是已知破坏两种蛋白质之间相互作用的化合物，这两种蛋白质与各种类型的癌症有关。设想未来的合作研究将评估目前可获得的化合物对生物靶点的作用。此外，本研究开发的新化学试剂和合成方法将在化学合成和药物化学领域得到广泛应用。

The development of new medicines (drug discovery) is essential to improve the health of the world's population. Tackling current medical needs requires drugs that will work in new ways. Therefore, more complex biological interactions are being investigated as targets. However, finding good starting points for drug development that will act against these complex biological targets presents a formidable challenge.Historically, starting points for drug development, known as lead compounds, came from natural small molecules that bind to the target. However, these are often not available, particularly in complex binding interactions. The screening of compound collections in the pharmaceutical industry has also been largely unsuccessful in finding lead compounds for more complex targets. This is because industrial compound collections are often clustered around relatively few structural types and are frequently reliant on flat (non-chiral) structures. Alternative methods are required for the generation of more diverse and 3-dimensional (chiral) molecules that may function as drug-leads. Indeed the pharmaceutical industry is currently interested in focussing on fewer, higher quality lead compounds.This research will develop new chemical methods to enable the synthesis of diverse molecular frameworks with the potential to be lead compounds in drug discovery. These frameworks will be centred around chiral (3-D) heterocycles. Heterocycles are carbon based ring structures that contain at least one heteroatom in the ring (i.e. an oxygen, nitrogen or sulphur atom) and are frequently essential components of drug compounds. Chiral heterocycles in particular offer ideal properties for quality lead compounds, being small with desirable physical properties as well as having a defined 3- dimensional shape, which is crucial to structural and binding interactions with biological systems.The synthesis of these complex heterocyclic molecules from simple, readily available starting materials is of fundamental interest and a major synthetic challenge. The key synthetic innovation of this proposal is the invention, development and application of new chemical reagents to achieve this goal. These reagents contain multiple functionality, important in performing multiple roles in the synthesis. Synthetic methods will be developed for three classes of chiral heterocycles with control of the 3-D shape. Furthermore these synthetic methods will allow a wide variety of chemical groups to be introduced directly onto the heterocyclic core of the molecule. This will enable rapid access to diverse molecular frameworks not currently well represented in industrial compound collections.Compounds generated by these new methods are of interest as potential lead compounds against a wide variety of biological targets. To demonstrate this, a series of analogues will be prepared of a compound known to disrupt the interaction between two proteins that is implicated in various types of cancer. Future collaborative research is envisaged to evaluate the now accessible compounds against biological targets. Furthermore, the new chemical reagents and the synthetic methods developed in this research will be widely applicable in fields of chemical synthesis and medicinal chemistry.