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

合成化学家一直热衷于从现成的起始材料中创造分子复杂性。开发一种药物的典型成本超过20亿美元，进入市场所需的时间约为14年。由于损耗率非常高，因此更快、更经济的创建这些实体的过程受到欢迎。导致药物正确形状的选择性过程确保它正确地适合其3D生物手性蛋白质靶标。此外，药物需要大规模生产。我们最近描述了一系列“原子经济”的金属催化多组分反应，使用所有原子来创建具有3D形状的复杂结构，以补充蛋白质靶标的复杂性。此外，催化性质确保能源消耗，废物产生，溶剂使用最小，因此具有大规模生产的潜力。此外，催化剂非常容易制造，在空气中稳定，使其易于获得和可扩展，并且我们可以监控和优化新反应而无需昂贵的惰性气体。我们的目标是证明这些催化反应具有现实世界的应用程序，如在PROTAC（蛋白质水解靶向嵌合体）分子的设计，有针对性的蛋白降解，目前激烈的学术和商业利益的一个领域。PROTAC诱导泛素化机制标记蛋白质，以便通过蛋白酶体进行回收。结构导向药物设计和生物分析可以形成一个反馈回路，我们可以优化PROTAC，以提高其选择性和性能，如溶解性，渗透性和稳定性。这些发现将深刻影响PROTAC和连接剂化学的设计和优化，一般，学术团体与领先的英国工业合作伙伴的结合将使我们能够实现我们的目标。

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.