Novel molecular photoswitches for use in chemical biology

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Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications that capitalise on the high temporal and spatial precision of using light as a stimulus. The recently established field of photopharmacology uses photoswitchable ligands that are selective for a specific cellular target, such as a receptor or an enzyme, and are employed as therapeutic entities. These ligands undergo a change in shape, flexibility, or electronic properties upon irradiation with light that leads to a change in the affinity for their cellular target; therefore, they exhibit a light-dependent therapeutic activity. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one or both of the aryl rings from the conventional azobenzene class has been replaced with a five-membered heteroaromatic ring. Within this class, our group recently discovered the arylazopyrazoles, which offer quantitative photoswitching and high thermal stability of the Z isomer (half-lives of up to about 1000 days). We have developed excellent understanding of the structure-property relationships for a wide array of comparable azoheteroaryl photoswitches and are now placed to explore these state-of-the-art systems for photopharmacology applications. This proposal will seek to develop photopharmacological agents and improved designs for biological application. A range of targets will be explored, with a particular focus on methyltransferases.Strategic Themes: Healthcare Technologies; Physical SciencesResearch Areas: Analytical science; Physical Sciences: Chemical Biology and Biological Chemistry