Glutathione Conjugates as the Activated Form of Chalcones for Glutathione S-Transferase Inhibition

Abstract

Chloro-substituted 4′-phenylchalcones inhibited glutathione S-transferase (GST) in vitro. They first reacted with the reduced glutathione (GSH) to give the GSH conjugates of the Chalcones, which actually inhibited GST. The chemical structure of the conjugates was inferred from the ultraviolet spectral change during conjugation and established by synthesis as the GSH addition product on the β-position of the α, β-unsaturated ketone moiety of the chalcone. Among the GSH conjugates of 2-, 3- and 4-chloro- and 2, 3-, 2, 4-, 2, 6- and 3, 4-di-chloro-4′-phenylchalcones, 2-chloro-compound was remarkable in GST inhibition, but others are also active. The overall inhibition of GST by chalcones depends mostly on the rate of GSH conjugation which is affected by the position and number of chloro-substituents. The GSH conjugation of 4-chloro-compound was, if any, very slow and gave lower GST inhibition, although its GSH conjugate gave inhibition comparable to others. The mode of GST inhibition seemed incompetitive as shown with the GSH conjugate of 2-chloro-4′-phenylchalcone, which had the K_i value comparable to that of tridiphane.