Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as potential antitumor agents.

摘要: We have reported previously that unsymmetrical disulfide inhibitors of the human thioredoxin/thioredoxin reductase redox system (hTrx/TR) possess antitumor activity. broadened search for more potent and evaluated a large range mono- bis-disulfide compounds, prepared using parallel syntheses. Reaction isothioisourea-HCI salts (R') or bis-salts (R) with aromatic aryl thiols (R") in wells 96-well plates produced >450 derivatives structures R"SSR' R"SSRSSR". The excellent yield purity disulfides provided sufficient material evaluations enzyme inhibition cytotoxicity. Selection criteria based on IC50 values hTrx/TR cytotoxicities identified agents subsequent scale-up syntheses vivo These studies confirmed original activities synthesized validated synthetic approach. Structure-activity information derived from data allow number generalizations. most Trx contained two heteroatoms ortho to moiety an functionality. thioalkylating moieties had greatest activity one branch point alpha disulfide. In absence branching, was observed electron withdrawing functionalities. Bis-disulfides showed patterns which depended chain length, optimum when units were separated by 3.9 A, similar distance separating thioredoxin active site cysteine residues. From selected syntheses, three compounds studied their against tumor xenografts scid mice. One analogues discovered through combinatorial syntheses/screening inhibition, 1-phenylethyl 2-imidazolyl disulfide, N1 (ProlX agent PX-C5), has demonstrated MCF-7 breast cancer HL-60 leukemia, thus validating this approach novel drug discovery.