Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: A Transformative Disconnection for Drug Discovery

饱和杂环硼酸酯的立体特异性 Csp3-Csp2 交叉偶联：药物发现的变革性断开

• 批准号: EP/V048139/1
• 负责人: Peter O'Brien
• 金额: $ 25.79万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV048139%2F1
• 关键词: Stereospecific; Csp3; Csp2; Cross; Coupling

Cyclic oxygen- and nitrogen-containing compounds (ring compounds that contain a series of carbon atoms and an oxygen or nitrogen atom) are very common structural units in a wide range of commercial pharmaceuticals. One example is Paroxetine which was developed by GlaxoSmithKline for the treatment of depression. There is a growing interest for medicinal chemists in the pharmaceutical industry to work on chiral drug structures. Chiral molecules are compounds which exist in mirror image forms (just like our hands) - drugs need to be prepared with one handedness (known as single enantiomers) as each enantiomer can have different biological properties. One of the most widely used processes in the pharmaceutical industry to synthesise drug molecules is the Suzuki-Miyaura cross-coupling reaction, the importance of which was recognised with the award of the 2010 Nobel Prize. However, the Suzuki-Miyaura reaction has not been used to directly prepare chiral drug motifs - there is currently no method for the general Suzuki-Miyaura cross-coupling of chiral saturated heterocyclic boronates with aryl halides. This project will deliver such a process to enable transformative and non-traditional disconnections, fundamentally changing the way that three-dimensional saturated nitrogen- and oxygen-containing heterocycles are constructed. Reaction discovery and optimisation of suitable catalytic protocols will be driven by automated high throughput experimentation, rich data analysis and rigorous mechanistic studies. The ubiquity of chiral cyclic molecules containing in FDA-approved drugs ensures that the process will be an enabling and transformative technology for drug discovery in the pharmaceutical industry. Finally, there will be an opportunity to use our new methodology in the optimisation of fragment hits against proteins of interest for the treatment of covid-19.

环状含氧和含氮化合物（含有一系列碳原子和一个氧或氮原子的环化合物）是广泛的商业药物中非常常见的结构单元。一个例子是帕罗西汀，它是由葛兰素史克公司开发的用于治疗抑郁症。在制药工业中，药物化学家对手性药物结构的研究越来越感兴趣。手性分子是以镜像形式存在的化合物（就像我们的手一样）-药物需要用一种手性（称为单一对映体）制备，因为每种对映体可以具有不同的生物学特性。制药工业中最广泛使用的合成药物分子的方法之一是铃木-宫浦交叉偶联反应，其重要性获得了2010年诺贝尔奖的认可。然而，Suzuki-Miyaura反应尚未用于直接制备手性药物基序-目前还没有手性饱和杂环硼酸酯与芳基卤化物的一般Suzuki-Miyaura交叉偶联的方法。该项目将提供这样一个过程，以实现变革性和非传统的断开，从根本上改变三维饱和含氮和含氧杂环的构建方式。反应发现和合适的催化方案的优化将由自动化高通量实验、丰富的数据分析和严格的机理研究驱动。FDA批准的药物中所含的手性环状分子的普遍存在确保了该过程将成为制药行业药物发现的一种使能和变革性技术。最后，将有机会使用我们的新方法来优化针对目标蛋白质的片段命中，以治疗新冠肺炎。