Towards efficient and scalable syntheses of fluorinated drug candidates

实现氟化候选药物的高效且可扩展的合成

• 批准号: 2106076
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2106076
• 关键词: Towards; efficient; scalable; syntheses; fluorinated

A major research project in the Linclau group concerns fundamental investigations into how fluorine introduction influences properties such as molecular lipophilicity and hydrogen bond properties of adjacent functional groups. Lipophilicity (logP) is linked to the capacity of compounds to pass cell membranes and is a main parameter in the drug discovery process. The hydrogen bond (H-bond) is the most important specific interaction between a molecule and its local environment, and is of utmost relevance in ligand-protein binding, supra-molecular chemistry, catalysis etc.A key aim of our research is to apply of our findings in the pharmaceutical arena in order to maximise its impact. In this regard, we have explored a wide range of steroid fluorinations aimed at achieving target selectivity and affinity, based on rational designs guided by our fundamental research. Interestingly, unexpected side-products in the fluorination reactions have also been converted to final targets as an efficient way to increase diversity. This approach has been successful in that a number of Southampton-designed hits have been discovered towards neurodegenerative disease, and a selection will be taken forward to clinical trials by NZP UK.This CASE project aims the upscaling of a range of such hits. Typically, the synthesis of hits that arose from unexpected side reactions are typically low-yielding and difficult to isolate. The re-synthesis of these hits using the way they were obtained would be very inefficient, and thus require a modified or completely new synthesis. Hence, objective 1 regards the design and optimisation of novel syntheses for a number of these hits. Objective 2 regards the upscaling of these syntheses, which will be carried out on placement.

Linclau小组的一个主要研究项目涉及氟引入如何影响相邻官能团的分子亲油性和氢键性质等性质的基础研究。亲脂性（logP）与化合物通过细胞膜的能力有关，是药物发现过程中的主要参数。氢键（H-键）是分子与其局部环境之间最重要的特异性相互作用，并且在配体-蛋白质结合、超分子化学、催化等方面具有极其重要的意义。我们研究的一个关键目标是将我们的发现应用于制药竞技场，以最大限度地发挥其影响。在这方面，我们已经探索了广泛的类固醇氟化，旨在实现目标的选择性和亲和力，基于我们的基础研究指导下的合理设计。有趣的是，作为增加多样性的有效方法，在生物降解反应中的意外副产物也被转化为最终目标。这种方法已经取得了成功，因为已经发现了一些南安普敦设计的命中对神经退行性疾病，并选择将由NZP UK进行临床试验。这个CASE项目旨在扩大一系列这样的命中。通常，由意外的副反应引起的命中物的合成通常是低产的并且难以分离。使用它们获得的方式重新合成这些命中将是非常低效的，并且因此需要修改的或全新的合成。因此，目标1涉及这些命中数的新颖合成的设计和优化。目标2涉及这些合成的升级，将在放置时进行。