Photogeneration of Quinone-Methides as Latent Electrophiles for Lysine-Targeting

October 11, 2018


Photogeneration of Quinone-Methides as Latent Electrophiles for Lysine-Targeting


Raul Perez-Ruiz, Oscar Molins-Molina, Emilio Lence, Concepción González-Bello, Miguel A Miranda, M. Consuelo Jiménez




The Journal of Organic Chemistry


Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon bind-ing with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles − quinone methides (QM) − for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@ HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity towards lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in sub-domains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in sub-domain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA sub-domains and the covalent modification mechanism. These studies open the oppor-tunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.




Fluorescence, Protein structure, Ligand binding, Chemical stability, Organic chemistry, Biochemistry