Chalcone derivatives inhibit glutathione S-transferase P1-1 activity: insights into the interaction mode of alpha, beta-unsaturated carbonyl compounds.

Resistance to chemotherapeutic drugs has long been a considerable barrier to successful treatment of many cancers and over-expression of glutathione S-transferase P1-1 is correlated to carcinogenesis and resistance of cancer cells against chemotherapeutic agents. This study throws light on the role of chalcone derivatives, a new class of glutathione S-transferase P1-1 inhibitors potentially to overcome glutathione S-transferase P1-1-mediated chemotherapy resistance. Nineteen alpha-substituted chalcone derivatives were synthesized and their in vitro inhibitory effects on glutathione S-transferase P1-1 were determined. We interestingly found that most of these compounds showed inhibitory effect on glutathione S-transferase P1-1 activity. In addition, molecular field-based similarity analysis provides the necessary three-dimensional molecular field properties of alpha, beta-unsaturated carbonyl derivatives to inhibit glutathione S-transferase P1-1 activity. Thus, these compounds have great potential to be developed into novel chemotherapeutic sensitizers.