The kinetics of uptake and accumulation of 3,6-bis-ω-diethylamino-amyloxyxanthone by the human malaria parasite Plasmodium falciparum

Jane Xu Kelly, R. W. Winter, Anda Cornea, David H. Peyton, David J. Hinrichs, Michael Riscoe

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Malarial parasites rely on the digestion of hemoglobin during the intra-erythrocytic stage. The enzymatic degradation of hemoglobin yields amino acids for parasite survival, and free heme which is detoxified by conversion to an aggregate of dimeric heme known as hemozoin. Xanthones have been found to subvert this process by formation of soluble drug-heme complexes. We have optimized the simple hydroxyxanthone structure to include side chains with protonatable nitrogen atoms to enhance interaction with the propionate groups of heme and to target the drug to the parasite digestive vacuole. One member of this optimized class of compounds, 3,6-bis-ω-diethylaminoamyloxyxanthone (C5), was used as a prototype for mechanistic studies. By HPLC analysis we demonstrate that the drug accumulates in the digestive vacuole from 5 to ∼33 000 μM within 1 h of exposure to parasitized red cells. Confocal fluorescence microscopy was used to visualize the accumulation process directly and to document the colocalization of the drug with the acidophilic dye, LysoTracker Red.

Original languageEnglish (US)
Pages (from-to)47-54
Number of pages8
JournalMolecular and Biochemical Parasitology
Volume123
Issue number1
DOIs
StatePublished - Aug 7 2002

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Keywords

  • Chemotherapy
  • Confocal fluorescence microscopy
  • Digestive vacuole
  • Heme
  • Hemozoin
  • Malaria
  • Plasmodium falciparum
  • Xanthone

ASJC Scopus subject areas

  • Parasitology
  • Molecular Biology

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