Disulfide Reductases of Parasites and Cancer Cells as Targets of Medicinal Chemistry

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New drugs against parasitic and cancer diseases are urgentlyand continuously needed. The aim of this interdisciplinaryproject is to substantiate disulfide reductase inhibitors asantiparasitic and cytostatic agents. Such compounds are activeper se but, in addition, they can reverse thiol-basedresistance against other drugs in parasites and tumour cells.Our strategy is based on the synthesis of inhibitors andsubversive substrates of the selected targets, namely theglutathione reductases (GR) of the malarial parasite Plasmodiumfalciparum and man, the thioredoxin reductases (TrxR) of P.falciparum and man, and - as a biological standard -trypanothione reductase (TR) from Trypanosoma cruzi. Inparticular, the preparation of focused chemical libraries willbe developed by the French team (RT 1) in order to introducestructural diversity and to optimize the most potent inhibitorsof the respective enzymes, using both classical medicinalchemistry and parallel synthesis. With the expectation ofsynergistic effect, novel double-headed prodrugs will beprepared. Such compounds consist of a disulfide reductaseinhibitor linked bioreversibly to a drug that is known to bedirected to a specific subcellular compartment. Research teams2 (glutathione-dependent redox networks) and 3(thioredoxin-dependent redox proteins) will examine themodifications of enzyme structure and function exerted by thenovel lead compounds. Furthermore their effects on malarialparasites and on human cancer cell lines will be studied, withspecial emphasis on strains and cell lines that are resistanttowards the most commonly used drugs in chemotherapy, i.e. theantimalarial chloroquine (CQ) and the anticancer agentcis-dichlorodiamminoplatinum. New compounds will be selected aspotential antiparasitic or cytostatic drug candidates by thefollowing criteria: high antiparasitic or antineoplasticactivity, low toxicity against normal human cells, decrease ofintracellular glutathione, thioredoxin or trypanothione levels,reversal of drug resistance, and tolerance by blood cells ofpersons with G6PD deficiency. The lead compounds will beproduced by chemical bulk procedures and serve as candidatesfor in vivo experiments using mouse models. Validation of theselected targets will be achieved by correlating the molecularmode of action and the in vivo activities of the drugcandidates. The synergy of the three research teams has stoodthe test of practice.