Pr Matthew FUCHTER
Department of Chemistry, Imperial College London. m.fuchter@imperial.ac.uk
New approaches for the discovery of photopharmacological agents.
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 photopharmacology1 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.
This talk will give an overview of our recent discovery of a new class of photoswitch, the azopyrazoles2-4, which offer quantitative photoswitching and high thermal stability of the Z isomer (half-lives of up to ∼1000 days). It will then describe how these switches, together with related heteroaromatic switch designs can enable the discovery of next generation photopharmacological agents, both in terms of target-based design5,6 and new discovery methodologies.
References
(1) Fuchter, M. J. J. Med. Chem. 2020, 63, 11436.
(2) Weston, C. E.; Richardson, R. D.; Haycock, P. R.; White, A. J. P.; Fuchter, M. J. J. Am. Chem. Soc. 2014, 136, 11878.
(3) Calbo, J.; Weston, C. E.; White, A. J. P.; Rzepa, H.; Contreras-García, J.; Fuchter, M. J. J. Am. Chem.Soc. 2017, 139, 1261.
(4) Gonzalez, A.; Odaybat, M.; Le, M.; Greenfield, J. L.; White, A. J. P.; Li, X.; Fuchter, M. J.; Han, G. G. D. J. Am. Chem. Soc. 2022, 144, 19430.
(5) Weston, C. E.; Kraemer, A.; Colin, F.; Yildiz, O.; Baud, M. G. J.; Meyer-Almes, F. –J.; Fuchter, M. J. ACS Infect.Dis. 2017, 3, 152.
(6) Lam, P. –Y.; Thawani, A. R.; Balderas, E.; White, A. J. P.; Chaudhuri, D.; Fuchter, M. J.; Peterson, R. J. Am.Chem. Soc. 2020, 142, 17457.
