Disulfide reductases of parasites and cancer cells as targets of medicinal chemistry

• Applicant: Dr. Stephan Gromer
• Subject Area: Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2002 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5384263

New drugs against parasitic and cancer diseases are urgently and continuously needed. The aim of this interdisciplinary project is to substantiate disulfide reductase inhibitors as antiparasitic and cytostatic agents. Such compounds are active per se but, in addition, they can reverse thiol-based resistance against other drugs in parasites and tumour cells. Our strategy is based on the synthesis of inhibitors and subversive substrates of the selected targets, namely the glutathione reductases (GR) of the malarial parasite Plasmodium falciparum and man, the thioredoxin reductases (TrxR) of P. falciparum and man, and - as a biological standard - trypanothione reductase (TR) from Trypanosoma cruzi. In particular, the preparation of focused chemical libraries will be developed by the French team (RT 1) in order to introduce structural diversity and to optimize the most potent inhibitors of the respective enzymes, using both classical medicinal chemistry and parallel synthesis. With the expectation of synergistic effect, novel double-headed prodrugs will be prepared. Such compounds consist of a disulfide reductase inhibitor linked bioreversibly to a drug that is known to be directed to a specific subcellular compartment. Research teams 2 (glutathione-dependent redox networks) and 3 (thioredoxin-dependent redox proteins) will examine the modifications of enzyme structure and function exerted by the novel lead compounds. Furthermore their effects on malarial parasites and on human cancer cell lines will be studied, with special emphasis on strains and cell lines that are resistant towards the most commonly used drugs in chemotherapy, i.e. the antimalarial chloroquine (CQ) and the anticancer agent cis-dichlorodiamminoplatinum. New compounds will be selected as potential antiparasitic or cytostatic drug candidates by the following criteria: high antiparasitic or antineoplastic activity, low toxicity against normal human cells, decrease of intracellular glutathione, thioredoxin or trypanothione levels, reversal of drug resistance, and tolerance by blood cells of persons with G6PD deficiency. The lead compounds will be produced by chemical bulk procedures and serve as candidates for in vivo experiments using mouse models. Validation of the selected targets will be achieved by correlating the molecular mode of action and the in vivo activities of the drug candidates.

• DFG Programme: Research Grants
• Participating Person: Dr. Elisabeth Davioud-Charvet