Overcoming multi-drug resistance using GST-activated anticancer agents

Multi-drug resistance (MDR) is an important challenge in medicinal enzymology. Since the pi isozyme of human Glutathione S-transferase (hGSTP1-1) is often over-expressed in MDR tumor cells, one strategy to overcome MDR is to make substrates that will become more toxic in the presence of hGSTP1-1. A class of 2-crotonyloxymethylcycloalkenone compounds (COMCs), derivatives of a cytotoxic metabolite isolated from Streptomyces griseosporeus , was investigated as substrates for hGSTP1-1. Catalysis was found to involve the formation of a cytotoxic exocyclic enone that accounts for the anti-tumor activities of these compounds.;Other workers have found that nitric oxide induces apoptosis in tumor cells when delivered by nitric oxide donors -- diazeniumdiolates.;A diazeniumdiolate derivative of COMC, O2-(2-methyl-cyclohexen-1-one) [1-(N, N-diethylamino)diazen-1-ium-1,2-diolate] (COMC-NO) was synthesized. The kinetic parameters from the reaction between COMC-NO and glutathione were obtained: non-enzymatic second order rate constant = 0.109 mM-1min -1 and kcat/KM = 0.56 x 103 mM-1 min-1. These rate constants suggest possible MDR selectivities.;The synthesis of lactam derivative of COMC was attempted unsuccessfully.