Chapter 20 Small-Molecule Inhibitors of Glutathione S-Transferase P1-1 as Anticancer Therapeutic Agents

Abstract

Publisher Summary The important function of Glutathione S-Transferase (GST) is the detoxification of endogenous as well as exogenous substances via conjugation with glutathione. Studies of several cancer tissues have revealed the overexpression of different GST isozymes, with GST P1-1 (GST Pi, GST π) being the most predominant. For this reason, GST P1-1 is regarded as a potential tumor marker. The high expression levels of GST P1-1 (up to 2.7% of the total cytosolic protein), combined with its detoxification role against xenobiotics, make GST P1-1 a major player responsible for drug resistance in patients undergoing anticancer chemotherapy. This chapter discusses inhibitors of GST P1-1 based on their mode of action such as suicide inhibitors, competitive inhibitors, and GST P1-1-activated prodrugs. Suicide or irreversible inhibitors of GST P1-1 include agents that bind covalently to glutathione, thereby forming thioether adducts that are stabilized at the active site of the enzyme. These agents include activated aromatic systems, epoxides, esters, and Michael acceptors such as ethacrynic acid, cycloalkenones, and haloenol lactones. Competitive inhibitors of GST P1-1 fall under two categories: non-glutathioneand glutathione-based compounds. GST P1-1-activated prodrugs undergo GST P1-1 catalyzed breakdown to release a molecule that is the active species responsible for the anticancer effect.