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

• 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

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.

新药的开发(药物发现)对于改善世界人口的健康至关重要。满足当前的医疗需求需要以新的方式发挥作用的药物。因此，更复杂的生物相互作用正被作为研究的目标。然而，为针对这些复杂的生物靶点的药物开发找到良好的起点是一个艰巨的挑战。从历史上看，药物开发的起点，即所谓的先导化合物，来自与靶标结合的天然小分子。然而，这些通常是不可用的，特别是在复杂的结合相互作用中。制药业对化合物集合的筛选也在很大程度上未能成功地为更复杂的目标寻找先导化合物。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。需要其他方法来产生更多样化和更三维的(手性)分子，这些分子可能起到药物先导的作用。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，使各种分子骨架的合成能够成为药物发现中的先导化合物。这些骨架将围绕手性(3-D)杂环。杂环是碳基的环结构，在环中至少含有一个杂原子(即氧、氮或硫原子)，通常是药物化合物的基本成分。尤其是手性杂环为高质量的先导化合物提供了理想的性质，它体积小，具有理想的物理性质，并且具有明确的三维形状，这对与生物系统的结构和结合作用至关重要。这一方案的关键综合创新是为实现这一目标而发明、开发和应用新的化学试剂。这些试剂包含多种官能团，对于在合成中扮演多种角色很重要。将开发三类可控制三维形状的手性杂环的合成方法。此外，这些合成方法将允许各种化学基团直接引入到分子的杂环核心上。这将使人们能够快速获得目前在工业化合物收集中没有很好代表的各种分子骨架。通过这些新方法产生的化合物作为潜在的先导化合物对广泛的生物靶标是有兴趣的。为了证明这一点，将准备一系列类似物，其中一种化合物已知可以破坏与各种癌症有关的两种蛋白质之间的相互作用。预计未来的合作研究将对照生物目标评估目前可获得的化合物。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具有广泛的应用前景。

项目成果

Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle "Stitching" by N-H Insertion and Cyclization

一锅法快速组装饱和氮杂环：通过 N-H 插入和环化实现重氮杂环“缝合”

• DOI: 10.1002/ange.201812925
• 发表时间: 2018
• 期刊: Angewandte Chemie
• 作者: Boddy A

Studies on the synthesis of a-iodoaziridines and improved conditions for the synthesis of alkyl-a-iodoaziridines using ClMgCHI2

ClMgCHI2 合成α-碘氮丙啶的研究及烷基-α-碘氮丙啶合成条件的改进

• DOI: 10.1016/j.tet.2015.05.098
• 发表时间: 2015
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Boultwood T

Synthesis and purification of iodoaziridines involving quantitative selection of the optimal stationary phase for chromatography.

碘氮丙啶的合成和纯化涉及定量选择色谱的最佳固定相。

• DOI: 10.3791/51633
• 发表时间: 2014
• 期刊: JoVE
• 作者: Boultwood T