REDOX-ACTIVE DISULFIDES - THE THIOREDOXIN SYSTEM AS A DRUG TARGET

Thioredoxin, and particularly extracellular thioredoxin, presents an a ttractive target for developing novel agents to treat cancer. Our stud ies have involved the examination of a series of alkyl 2-imidazolyl di sulfides as inhibitors of the growth-stimulatory activity of the thior edoxin system. We originally determined the disulfides to be weak reve rsible inhibitors of thioredoxin reductase. Subsequently, we have show n that alkyl 2-imidazolyl disulfides interact directly with thioredoxi n, thioalkylating critical cysteine residues or causing dimerization o f the protein leading to its loss of biological activity. One of the a nalogues that binds to thioredoxin, 1-methylpropyl 2-imidazolyl disulf ide (1V-2), selectively inhibits the thioredoxin-dependent growth of t umor cells in culture and has antitumor activity against MCF-7 and HL- 60 tumors in vivo. Our work involves the development of a parallel com binatorial synthetic method to produce a large number of disulfide ana logues at one time. These analogues, which differ sterically, electron ically, and physically, were produced in a 96-well plate. The biologic al activity of these analogues was evaluated, also in the 96-well plat e format. This rapid method of evaluating biological activity is a mea ns to identify agents with specificity for inhibition of the thioredox in system, and may provide novel antitumor agents with activity agains t solid tumor cancers.