Selective inhibitors of cellular redox homeostasis enzymes

The cellular redox system has a huge range of different vital properties, from the neutralization of reactive oxygen and nitrogen species to drug resistance. Also, redox balance is crucial for the progression of growth and the proliferation of tumor cells. Suchmajor systems are thioredoxin and glutathione systems. The enzymes that catalyze reactions in these systems, thioredoxin reductase and glutathione reductase, are promising targets in various human diseases. These enzymes possess a certain catalytic feature, i.e., an ability to promote the reduction of selenide–sulfide and disulfide groups, through which electrons are transferred for further oxidation–reduction processes on the protein. The increased expression of redox enzymes has been proven in tumor cells compared to normal cells.

In our study, we synthesized derivatives of oxazolones, molecules with an electron-deficient part, which could be potential inhibitors of redox enzymes. The derived molecules were screened for their ability to inhibit thioredoxin reductase and glutathione reductase on lung carcinoma cell lysates, and active candidate molecules were also selected. An analysis of the obtained enzymatic reaction rate change data made it clear that the molecules we synthesized tended to inhibit thioredoxin reductase more effectively, most likely due to their higher affinity for selenocysteine. Two molecules with a common 4-nitrostyryl-oxazolone moiety that were more effective as inhibitors of glutathione reductase were also identified. Selective binding studies with cysteine and selenocysteine using mass spectrometry were carried out for the selected molecules. The selected molecules were also tested for their cytotoxic activity against lung carcinoma cells.