Probes: Addition of photo-reactive groups

Click the structures to view the 3D models

The photo-reactive aromatic diazirine (red) is a compact and chemically stable moiety. It is integrated into the right-hand side of the HEA scaffold as it structurally mimics the benzyl substituent. Additionally, a terminal alkyne group (green) was introduced at the piperazine moiety, as this modification does not compromise the probe’s binding affinity, and cyclic or tertiary amides are generally tolerant to structural changes. Upon UV exposure, the diazirine undergoes activation, enabling the formation of covalent bonds with binding residues, facilitating precise mapping of ligand-protein interactions.

As shown above, prior to UV exposure the LUMO is localised on the diazirine three membered ring. Upon UV irradiation, a non-bonding electron from the nitrogen is excited into the LUMO of the N=N anti-bonding orbital. This electronic transition lowers the LUMO energy, weakening the C-N bonds which facilitates the homolytic cleavage of the bond, producing the highly reactive carbene (blue).

M. Lisauskaitė, G. L. Nixon, C. M. Woodley, N. G. Berry, A. Coninckx, L. C. Qie, S. C. Leung, D. Taramelli, N. Basilico, S. Parapini, S. A. Ward, O. Vadas, D. Soldati-Favre, W. D. Hong and P. M. O’Neill, RSC Chemical Biology, 2024, 5, 19–29.

Y. Zhang, S. Vyas, C. M. Hadad and M. S. Platz, The Journal of Physical Chemistry A, 2010, 114, 5902–5912.