Expanding the understanding and applications of small ring polycyclic scaffolds

Small ring polycyclic organic molecules have emerged as high-potential 3D-rich molecular cores for drug discovery. This is because of their demonstrated ability to replace benzene rings as cores in drug molecules, which are undesirable due to their poor solubility and susceptibility to metabolic degradation. Bridged bicyclic hydrocarbons (BBHs) - a subset of these polycyclic scaffolds - can reproduce the positioning of substituents that would be typically attached to benzene rings, and thereby offer an alternative molecular 'core' to the aromatic parent. These benzene ring 'bioisosteres' also crucially bring benefits of improved physical and chemical properties, as well as higher metabolic stability, while maintaining biological activity. This global field of research has attracted attention across academia and industry, and is one of the 'hottest' areas of exploration in drug design. Building on our >5 years' expertise in the synthesis and reactivity of these motifs, our project team will deliver an array of ground-breaking discoveries in knowledge and understanding in this competitive and highly topical area of chemical space, accelerating applications of these motifs for the benefit of human health. We will achieve this goal through a multifaceted research programme that exploits the expertise of our team in small ring synthesis, theoretical chemistry, and pharmaceutical applications. We have identified five exciting Objectives that represent totally new directions for research in this competitive field. These include the development of new classes of BBH bioisostere, methods to decorate these rigid cores at a late stage of their synthesis, mechanistic tools to understand the fundamental reactivity of these molecules, and asymmetric processes that access chiral / non-symmetric BBHs. For many of these objectives, we have obtained preliminary results that provide confidence in the delivery of these ambitious goals; our team's expertise across experimental, theoretical and commercial medicinal chemistry research will bring the combination of skills to deliver on these objectives, and demonstrate applications that will enable uptake of this new chemistry. As these are all completely new directions of research in the BBH field, but contribute to a highly popular and topical area of medicinal chemistry, we expect wide application of the methods and structures developed by researchers in both academia and industry. The benefits will be most keenly felt by society at large, by accelerating the drug discovery process and offering new motifs for the design of future medicines. The fundamental understanding of reactivity we will develop will benefit a wide range of synthetic chemists, as we will establish a new dogma in how ring strain influences reactivity. Our connection to pharmaceutical company AbbVie will underline the importance of this research to the commercial sector, benefiting the both the UK and the global drug discovery industry.