Inhibition of glutathione S-transferases by photoactive calix[4]arene α-ketophosphonic acids

Abstract

Calix[4]arenes bearing photoactive α-ketophosphonic acid groups at the upper rim of the macrocycle were synthesized and evaluated as inhibitors of glutathione S-transferases. Irradiation at 365 nm increased the inhibition effects of some macrocyclic compounds on GSTP1-1 by more than two orders of magnitude. Calix[4]arene bis-α-ketophosphonic acids substituted at the lower rim by n-propyl or n-butyl groups showed IC50 values in the low micromolar range. Kinetics of the irreversible inhibition was described by pseudo-first-order rate constants dependent on inhibitor concentration. The values of second-order rate constants were higher for glutathione S-transferase from human placenta than for the enzyme from equine liver. Molecular docking suggested that photoactive macrocyclic compounds cover the active site of glutathione S-transferase, providing the possibility to modify the catalytically important amino acid residues during irradiation.