New Directions in Bioisostere Research

The development of new drug candidates relies on a number of factors - not only the bioactivity of the molecule in question, but also properties such as its solubility, its ability to permeate cell membranes, and its susceptibility to metabolism by the body. Compounds containing benzene rings, as are common in many pharmaceuticals, can display problems in all these areas.

One solution is to replace such problematic motifs with a chemical group that has the same size (and positions its substituents in the same way), but avoids these pharmacology issues. These groups are termed 'bioisosteres', and in this project, we seek to develop new approaches to 'bicyclopentanes', a functional group that is a bioisostere for benzene rings. In previous work by medicinal chemists, the bicyclopentane has proven to be an efficient substitute for benzene in medicinal chemistry settings, and as such there is a high level of interest in this field in the use of this functionality.

While some approaches to these molecules are known, the methods used are generally rather harsh, and limited in scope. In this project, we will develop a number of new methodologies to access this important motif, mainly based around contemporary uses of free radical chemistry, which operate under very mild conditions and therefore are able to tolerate the kinds of chemical groups that are found in drug molecules. Our work will also include first-of-kind examples of asymmetric bicyclopentane synthesis, and demonstrations of the technology by application to real-life drug molecules. Finally, we will spend a proportion of the project time on developing scalable routes for bicyclopentane synthesis, with a view to commercialisation of some of the most useful building blocks, which will enhance the uptake of our work by end-users in the wider scientific community.

This project seeks to develop new opportunities in bioisostere research by delivering novel, efficient strategies for the synthesis of functionalised bicyclopentanes (BCPs). This work has the potential to revolutionise the use of BCPs in medicinal chemistry, impacting on the ability of chemists to design drug candidates. These developments in turn will influence biomedical research, and lead to long term impact in the Healthcare Technologies field. The following impacts are envisaged:

Industrial impact:
Greatest impact is envisaged in industrial application of the chemistry we will develop, specifically in the pharmaceutical and agrochemical industries. BCPs are a high priority for research in these fields due to their favourable pharmacokinetic properties, and also their novelty in intellectual property space. From the industry perspective, the consequence of this impact could realistically be the development of BCP-containing drug / agrochemical candidates - creating further impact in the biomedical sciences.

Economic and societal impact:
The availability of new motifs for use in drug candidates has the clear potential to impact on the UK economy and society via the provision of better therapies, improving the standard and cost of healthcare. Economic benefit is also envisaged through commercialisation activities, where we anticipate high demand for BCP building blocks. Societal impact connects to the use of the drugs that we believe could arise from the incorporation of BCPs into drug candidates. While no BCP drugs have yet progressed to clinical use, it is clear from the significant interest in these motifs that future use is not unrealistic. Finally, outreach / public engagement activities will impact on the wider community, based on the direct connection between basic chemistry research and application in human health.

UK science base:
The reputation of UK science will be enhanced by the ambition and scope of this project, via delivery and dissemination of the results. The UK does not yet have a strong international standing in the bioisostere field - and in particular bicyclopentanes. This project will therefore position a UK science team at the forefront of this research area on a global stage. Additionally, much of the chemistry developed is groundbreaking in its own right - such as the successful demonstration of photoredox chemistry in tricyclopentane ring opening, which strengthens the UK science base in catalysis / synthetic methodology. Finally, significant consequences are also envisaged in UK medicinal chemistry research. To maximise this impact, the PI will organise two one-day UK bioisostere conferences in the course of the project (end of Year 2 and 4, see Pathways to Impact).

People impact:
The PDRA associated with this project will receive broad training in catalysis, synthesis, medicinal chemistry, and entrepreneurship; their collaboration with industry will provide a useful contact network, and an appreciation of the industrial landscape, in all delivering a highly skilled researcher to the workplace. The collaborator team will also benefit (both academic and industry) by establishing a world-leading research position in the bioisostere field. These results will therefore be expected to lead to new opportunities for all members of the team. The wider people impact of this work of course relates to the medicinal chemistry consequences of the research, where we will facilitate the design of new drugs with consequent benefits to human health.

We expect the benefits to the PDRA and collaborators to be realised within the timeframe of the grant. The societal and economic benefits will arise from uptake of our work by other users, and have a longer term impact. This will be facilitated by the commercialisation element of the project, as well as the modes of dissemination, which will bring our work closer to the end-user community.