Antileishmanial activities of aphidicolin and its semisynthetic derivatives.
Aphidicolin and a series of semisynthetic aphidicolan derivatives have been identified in in vitro tests as novel drugs with antiparasitic potential. All compounds have been tested against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major and against intracellular amastigotes of L. donovani in murine macrophages. The compounds showed antileishmanial activity at concentrations in the microgram range (50% effective concentration [EC(50)] = 0.02 to 1.83 microg/ml). The most active derivative (aphidicolin-17-glycinate hydrochloride) had EC(50)s of 0. 2 microg/ml against extracellular and 0.02 microg/ml against intracellular L. donovani parasites. To validate the pharmacological potential of tested drugs, pharmacological safety was determined by testing all compounds against two neoplastic cell lines (squamous carcinoma [KB] and melanoma [SK-Mel]) and against murine bone marrow-derived macrophages as host cells. With minor exceptions only for macrophages, tested aphidicolans did not show significant cytotoxicity (EC(50) > 25.0 microg/ml). Structure-activity relationships of these aphidicolan derivatives are discussed.
Kayser
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O
Institute of Pharmacy and Department of Pharmaceutical Biotechnology, Freie Universität, D-12169 Berlin, Germany. kayser@zedat.fu-berlin.de
Kiderlen
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AF
Bertels
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Siems
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K
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000981:Antiprotozoal Agents; D003470:Culture Media; D016590:Aphidicolin