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Details of Grant 

EPSRC Reference: EP/Y022211/1
Title: Cyclobutadiene Reloaded: A Generally Applicable Approach to Functionalised Four-Membered Heterocycles
Principal Investigator: Coote, Dr S C
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Key Organics Ltd
Department: Chemistry
Organisation: University of Bath
Scheme: Standard Research
Starts: 01 April 2024 Ends: 31 March 2027 Value (£): 520,944
EPSRC Research Topic Classifications:
Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
Chemicals Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
05 Jul 2023 EPSRC Physical Sciences Prioritisation Panel- July 2023 Announced
Summary on Grant Application Form
Whilst traditional medicine largely depended on the serendipitous discovery of biologically active molecules, contemporary medicinal chemistry often involves the design of new molecules that may not exist already, based on a deep understanding of the interaction of the proposed drug molecule with its biological target. This process is frequently aided by computers, which can design drug molecules with the required characteristics for the desired biological activity based on an understanding of how the drug will operate. Thus, modern drug discovery relies heavily on the availability of efficient methods to prepare new drug molecules, as well as the precursors to the drug molecules themselves.

Four-membered heterocycles are a class of rigid molecules that contain at least one heteroatom (an atom other than carbon - for example, oxygen, nitrogen or sulfur) arranged in a ring of four atoms. These molecules are of interest in drug discovery because their rigidity results in specific topologies that often interact better with biological targets than more "floppy" molecules. In particular, spirocyclic versions of these molecules (in which two rings of atoms are joined, sharing one atom in common) are especially promising as precursors to drug molecules. However, these molecules are very difficult to prepare, and the methods that do exist for their preparation are often specific to certain substitution (highly substituted examples are difficult to access), resulting in a limited range of these drug precursors being available.

This project aims to streamline the preparation of these spirocyclic four-membered heterocycles, by developing new methodology that will be applicable across all of the classes of heterocycle (i.e. irrespective of the heteroatom(s) contained within the ring). Thus, a library of simple spirocyclic drug precursors will be generated, which can then be further "decorated" using existing chemistries to produce bespoke drug molecules for specific applications. The new methodology will make use of a reagent named cyclobutadiene, which is extremely versatile but has seen limited use previously. Cyclobutadiene is extremely reactive, so it cannot be stored and must be prepared immediately as it is to be used, and previously, no convenient precursors were available for its generation. This project will develop new precursors to cyclobutadiene that allow the generation of cyclobutadiene under mild conditions, with several different variants of essentially the same precursor being developed for different applications. As a result, a generally applicable, modular preparation of four-membered heterocycles will be enabled, making these molecules available as precursors to new drugs.

To ensure that our methodology is broadly adopted, our products will be marketed in a timely fashion by our project partner Key Organics - a fine chemicals company with international reach. This will maximise the impact of our methodology, and ensure that our products are available not only to drug discovery researchers, but also to a wide variety of other sectors. Longer term, we aspire to develop further applications of our molecular scaffolds, not necessarily limited to drug discovery, but also in other areas requiring rigid, small-molecule motifs.

Key Findings
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Organisation Website: http://www.bath.ac.uk