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

获得手性杂环作为药物发现中潜在先导化合物的新策略

基本信息

批准号：
EP/J001538/1
负责人：
James Bull
金额：
$ 92.14万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FJ001538%2F1
关键词：
Novel strategies access chiral heterocycles

项目摘要

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.

新药物（药物发现）的开发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方式起作用的药物。因此，正在研究更复杂的生物学相互作用作为靶标。但是，为药物开发寻找良好的起点，将对这些复杂的生物学靶标作用构成巨大的挑战。从历史上讲，药物开发的起点（称为铅化合物）来自与靶标结合的天然小分子。但是，这些通常是不可用的，尤其是在复杂的结合相互作用中。制药行业中化合物收集的筛查在为更复杂的目标寻找铅化合物方面也在很大程度上没有成功。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，并且经常依赖于平坦的（非生产）结构。生成可能起药物铅的更多样化和三维（手性）分子所必需的替代方法。实际上，制药行业目前有兴趣将重点放在更少，更高质量的铅化合物上。这项研究将开发新的化学方法，以使能够综合各种分子框架，并有可能成为药物发现中的铅化合物。这些框架将围绕手性（3-D）杂环。杂环是基于碳的环结构，在环中至少包含一个杂原子（即氧，氮或硫原子），并且通常是药物化合物的必不可少的成分。尤其是手性杂环为优质铅化合物提供理想的特性，具有理想的物理特性以及具有定义的3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。这些复杂的杂种分子的合成来自简单的，易于使用的起始材料，具有基本的质量挑战，并且是主要的合成挑战。该提案的主要综合创新是新化学试剂的发明，开发和应用以实现这一目标。这些试剂包含多个功能，对于在合成中执行多个角色很重要。将开发出三类手性杂环并控制3-D形状的合成方法。此外，这些合成方法将允许将各种化学基团直接引入分子的杂环核。这将使当前在工业化合物集合中尚未很好地代表的不同分子框架的快速访问。这些新方法产生的功能是针对各种生物学靶标的潜在铅化合物。为了证明这一点，将准备一系列类似物，以破坏与各种类型癌症有关的两种蛋白质之间的相互作用。设想未来的合作研究来评估现在可访问的化合物针对生物学靶标。此外，本研究中开发的新化学试剂和合成方法将广泛适用于化学合成和药物化学领域。