Copper(II)-Catalyzed Atom and Step Economical Late Stage Functionalisation of Bioactive Compounds

铜（II）催化原子和生物活性化合物的经济后期功能化

• 批准号: 2889449
• 金额: --
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2889449
• 关键词: Copper; II; Catalyzed; Atom; Step

Synthetic chemists have always been fascinated with creating molecular complexity from readilyavailable starting materials.The typical cost of developing a drug is over 2 billion USD,and the timerequired to reach the market is approximately 14 years. With a very high attrition rate, faster, moreeconomical processes for creating these entities are welcome. Selective processes that lead to thecorrect shape of the drug ensure that it fits correctly in its 3D-biological chiral protein target. Moreover,drugs need to be made on a large scale.We have recently described a series of metal catalysedmulticomponent reactions that are "atom economical", using all atoms to create complicatedarchitectures with 3D shapes, to complement the complexity of protein targets.Moreover, the catalyticnature ensures that energy use, waste production, solvent use are minimal, so have the potential forlargescale production. Also, the catalysts are very easy to make and are stable in air, making themreadily available and scalable, and the fact that we can monitor and optimise new reactions withoutrequiring expensive inert gases. We aim to demonstrate that these catalytic reactions have real-worldapplications as in the design of PROTAC (proteolysis targeting chimeras) molecules for targeted proteindegradation, an area of intense current academic and commercial interest. PROTACs induce theubiquitination machinery to tag a protein for recycling by the proteasome. Structurally guided drug designand biological assays can form a feedback loop to our synthetic chemistry where we can optimise thePROTACs to improve their selectivity and properties, such as solubility, permeability,and stability.Thesefindings will profoundly influence the design and optimisation of PROTACs andlinker chemistry ingeneral, and the combination of academic groups with leading UK industrial partners will enable us toattain our goals.

合成化学家一直着迷于从可轻松的起始材料中产生分子复杂性。开发药物的典型成本超过20亿美元，而到达市场的时间大约为14年。欢迎使用很高的流失率，更快，更经济的过程来创建这些实体。导致药物形状的选择性过程可确保其正确适合其3D生物学手性蛋白靶标。此外，我们最近描述了一系列“原子经济”的金属催化剂分量反应，使用所有原子来创建具有3D形状的复杂的构造，以补充蛋白质靶标的复杂性。此外，催化剂非常易于制造，并且在空气中稳定，使它们可易于使用且可扩展，并且我们可以监视和优化新的反应，从而使昂贵的惰性气体与昂贵的惰性气体相关。我们的目的是证明，这些催化反应具有现实的应用，就像针对靶向蛋白结构的Protac（蛋白水解靶向嵌合体）分子的设计一样，这是一个强烈的当前学术和商业利益的领域。 Protac诱导泛素化机制标记蛋白质以通过蛋白酶体回收。结构引导的药物设计和生物学测定可以形成我们的合成化学反馈循环，在那里我们可以优化Protacs以提高其选择性和特性，例如溶解度，渗透性和稳定性。这些发现将深刻地影响Protacs和Linker Chemistry Chement and Inker Ankity and In Uk Indurolial and Andirial and Andirial and Andirial and Andirial and Andirial and Andirial and Andirial and Andirial and and Insirial and and and and。