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Elisabeth Davioud-Charvet Goal Design, synthesis and mechanism of disulfide reductase inhibitors and redox-cyclers that affect the redox equilibrium of parasites and cancer cells. Background The aim of our interdisciplinary research is to sub- stantiate NADPH-dependent 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 subversive substrates or catalytic inhibitors, fluorine-based suicide-substrates, uncompetitive inhibitors, photoreactive inhibitors (as tools for photoaffinity labeling studies) 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, the trypanothione reductase (TR) from Trypanosoma cruzi, and the thioredoxin-glutathione reductase (TGR) of Schistosoma mansoni. Research Highlights Our strategy for inhibitor optimization is based on the design and the synthesis of dual drugs that 10 Elisabeth Davioud-Charvet 1985-2001 PhD in Pharmaceutical and Chemical Sciences, Paris 11 University, then senior scientist at Centre National de la Recherche Scientifique (CNRS), France 2001-2002 Visiting scientist at the University of Michigan, USA since 2001 Research director at CNRS, France since 2002 Junior group leader at Biochemie-Zentrum der Universität Heidelberg (BZH) Drug Development against Disulfide Reductases from Parasites and Cancer Cells act as “Trojan horses” drugs consisting of a short chloroquine analogue – active against malaria per se – linked to a GR inhibitor. This strategy was validated in the current malaria project with new functionalized 4-aminoquinolines derivatives that were found to be active in the low nanomolar range against the erythrocytic stages of P. falciparum and in mouse malaria models. Besides the dual drugs, a series of low-weight naphthoquinones revealed potent antimalarial effects against chloroquine-sensitive and -resistant strains of Plasmodium falciparum both in vitro and in vivo (patent). Regarding the basic research part of the whole project introduction of fluorine allowed us to identify the enzymic intermediate – an enzymic species containing reduced flavin – responsible for GR-catalyzed naphthoquinone reduction. In future work the aim is to identify the relevant physiological binding site of these naphthoquinones, especially those inducing a cooperative behaviour in GR catalysis. For leishmania and trypanosomes various unsaturated Mannich bases acting by TR inactivation were produced and revealed potent trypanocidal effects against pentamidine-sensitive and -resistant strains of Trypanosoma brucei in vitro. Current efforts include the chemistry of 1,4-naphthoquinones and Mannich bases derivatives as antiparasitic drug-
candidates (against malaria, trypanosomiasis, and schistosomiasis), studies on the mechanism and the regulation of disulfide reductase in vivo (malaria, trypanosomiasis). Fig. 1: Synthesis of fluorine-based naphthoquinone derivatives as mechanism-based inhibitors of NADPHdependent glutathione reductases (GR). Fig. 2: X-ray structure of the human GR active site bound to the naphthoquinone-derived inhibitor. Fig. 3: Crystals of human GR alkylated by a fluorinebased inhibitor. Selected Publications 2004 - 2007 Friebolin, W., Jannack, B., Wenzel, N., Furrer, J., Oeser, T., Sanchez, C. P., Lanzer, M., Yardley, V., Becker, K., Davioud- Charvet, E. (2007) Antimalarial Trojan drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum. J. Med. Chem. In press. Kuntz, A. N., Davioud-Charvet, E., Dessolin, J., Sayed, A. A., Califf, L. L., Arnér, E. S. J., Williams D. L. (2007) Schistosome redox balance and thioredoxin glutathione reductase: An essential parasite enzyme and novel drug target. PLoS Medicine 4(6):e206, 1-16. Bauer, H., Fritz-Wolf, K., Winzer, A., Kühner, S., Little, S, Yardley, V., Vezin, H., Palfey, B., Schirmer, H., Davioud- Charvet E. (2006) A fluoro analogue of the menadione derivative 6-[2’-(3’-Methyl)-1’,4’-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme. J. Am. Chem. Soc. 128, 10784-10794. Urig, S., Fritz-Wolf, K., Réau, R., Herold-Mende, C., Toth, K., Davioud-Charvet, E., Becker, K. (2006) Undressing of phosphine gold(I) complexes as irreversible inhibitors of human disulfide reductases. Angew. Chem. Int. Ed. Engl. 45, 1881-1886. Lee, B., Bauer, H., Melcher, J., Ruppert, T., Rattray, L., Yardley V., Davioud-Charvet, E., Krauth-Siegel, R. L. (2005) Irreversible inhibition of trypanothione reductase by unsaturated Mannich bases: a divinylketone as key intermediate. J. Med. Chem. 48, 7400-7410. Millet, R., Urig, S., Jacob, J., Gromer, S., Moulinoux, J.-P., Becker, K., Davioud-Charvet E. (2005) Synthesis of 5-nitro- 2-furancarbohydrazides and their cis-diamminedichloroplatinum complexes as irreversible inhibitors of human thioredoxin reductase. J. Med. Chem. 48, 7024-7039. Biot, C., Bauer, H., Schirmer, R.H., Davioud-Charvet, E. (2004) 5-Substituted tetrazoles as bioisosters of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. J. Med. Chem. 47, 5972-5983. Elisabeth Davioud-Charvet* Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 504 D-69120 Heidelberg * delegate of CNRS, in the frame of a German French cooperation with the University of Heidelberg, Germany Phone Office: +49 (0)6221-54 4188 Phone Lab: +49 (0)6221-54 4293 Fax +49 (0)6221-54 5586 E-mail: elisabeth.davioud@bzh.uni-heidelberg.de Elisabeth Davioud-Charvet 11
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