Alkyl and aryl α-ketophosphonate derivatives as photoactive compounds targeting glutathione S-transferases

Abstract

In this article, photoactive alkyl and aryl α-ketophosphonate derivatives were studied as inhibitors of glutathione S-transferases (GSTs). The α-ketophosphonate monoesters were synthesized by sodium iodide-induced dealkylation of corresponding phosphonate diesters. The compounds being inactive toward the enzyme without UV light were activated by irradiation at 365 nm which caused inhibition of GSTs from equine liver and human placenta with micromolar IC50 values. Hetaryl α-ketophosphonate monoesters can also be potential candidates for the UV-dependent enzyme targeting. Inhibitory potency of the phosphonate monoesters was comparable to that of free phosphonic acid. No effects were observed in case of dialkyl α-ketophosphonates. The light-induced effects of the inhibitors were found to be related to decrease in maximum velocity but not to Michaelis constants of the enzyme-catalyzed reaction. The kinetics of a decrease in enzyme activity was described by pseudo-first order rate constants dependent on inhibitor concentration. The calculated second order rate constants indicated that the alkyl α-ketophosphonate monoesters can exhibit higher potency in comparison with that of aryl or hetaryl phosphonate derivatives.