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Triggers and Targets of Ascaridole Action in Leishmania

Project Leader
Rosenau Thomas, BOKU Project Leader
Duration:
01.07.2015-30.06.2018
Type of Research
Basic Research
Project partners
Institute of Pharmacology and Toxicology, Veterinärplatz 1, A-1210 Wien, Austria.
Contact person: Prof. Dr. Lars Gille;
Function of the Project Partner: Koordinator
Staff
BOKU Research Units
Division of Chemistry of Renewable Resources
Funded by
Fonds zur Förderung der wissenschaftlichen Forschung (FWF) , Sensengasse 1, 1090 Wien, Austria
Abstract
This proposed research project will elucidate the specific triggers of ascaridole (Asc) activation in these cells and the preferred targets that cause cytotoxicity in Leishmania and might contribute to selectivity. Specifically, the role of heme iron and the low molecular labile iron pool in Asc activation will be studied with electron spin resonance (ESR) spectroscopy. Mechanism studies will be supported by the synthesis of Asc-related endoperoxides and the use of non-endoperoxide Asc analogues to enable structure activity relationship studies. The role of selective toxicity will be addressed by comparison studies with monocyte/macrophage cell lines as well as with mammalian detoxification enzymes. Findings of the mechanism studies relevant for treatment will be verified in a mouse model of cutaneous leishmaniasis. Based on the details of the mechanism of action of Asc, the synergistic/antagonistic role of chemotherapeutic metal-chelating ligands in their action against Leishmania will be identified. The mechanism details revealed in this project will help to understand the conditions for effective application of Asc-related endoperoxides as antileishmanial drugs.
Keywords
Natural product chemistry; Organic chemistry;
Ascaridole; Leishmania; tocopherol derivatives; Vitamin E;
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