Design, Synthesis And Anticaner Activity Of α,β-Unsaturated Carbonyl Derivatives As GSTπ Inhibitors

Multidrug resistance (MDR) of tumor cells to chemotherapeutic agents is known to be the main reason for treatment failure in cancer chemotherapy. MDR mediated by glutathione S- transferases (GSTs) is an important reason of the drug resistance development of human tumor cells. Among the isoenzymes of GSTs, human GSTπ serves two different roles in the development of resistance toward chemotherapy agents through acting as phase II detoxification enzymes, and as regulators of the mitogen-activated protein kinase (MAPK) pathway. Increased expression of GSTπ was found to be correlated with the resistance of some chemotherapeutic agents in human tumor cells including colon, stomach, pancreas, uterine cervix, breast, lung cancers, melanoma, and lymphoma. Thus there is a potential to develop GSTπ inhibitors into apoptosis enhancers or agents of overcoming chemotherapy resistance.Ethacrynic acid (EA), an α,β-unsaturated carbonyl derivative, has been found to enhance the cytotoxicity of chemotherapeutic agents such as thiotepa, that is correlated with GSTπ inhibition. In addition to being a GSTπ inhibitor, EA also has been found to interact directly with glutathione(GSH) to form an EA-GSH conjugate that is also a GSTπ inhibitor. Taken EA as a lead compound, thirty seven of α,β-unsaturated carbonyl compounds were designed and synthesized. Their inhibitory activities on GSTπ and growth inhibition activity on tumor cells were determined. The chemical structures of the compounds,...