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Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.

ABSTRACT: The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well-known reactivity of the 1,2,4-trioxolane ring toward inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the subcellular localization of 1,2,4-trioxolanes in cultured Plasmodium falciparum parasites. Microscopy experiments revealed that a probe fluorescently labeled on the adamantane ring accumulated specifically in digestive vacuole-associated neutral lipid bodies within the parasite while an isosteric, but nonperoxidic, congener did not. Probes fluorescently labeled on the cyclohexane ring showed no distinct localization pattern. In their subcellular localization and peroxidative effects, 1,2,4-trioxolane probes behave much like artemisinin-based probes studied previously. Our results are consistent with a role for adamantane-derived carbon-centered radicals in the antimalarial action of 1,2,4-trioxolanes, as hypothesized previously on the basis of chemical reactivity studies.

SUBMITTER: Hartwig CL

PROVIDER: S-EPMC3236788 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.

Hartwig Carmony L CL Lauterwasser Erica M W EM Mahajan Sumit S SS Hoke Jonathan M JM Cooper Roland A RA Renslo Adam R AR

Journal of medicinal chemistry 20111109 23

The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well-known reactivity of the 1,2,4-trioxolane ring toward inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the subcellular localization of 1,2,4-trioxolanes in cultured Plasmodium falciparum parasites. Microscopy experiments reve ...[more]

PMID: 22023506

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Project description:BackgroundTo study the chemical determinants of small molecule transport inside cells, it is crucial to visualize relationships between the chemical structure of small molecules and their associated subcellular distribution patterns. For this purpose, we experimented with cells incubated with a synthetic combinatorial library of fluorescent, membrane-permeant small molecule chemical agents. With an automated high content screening instrument, the intracellular distribution patterns of these chemical agents were microscopically captured in image data sets, and analyzed off-line with machine vision and cheminformatics algorithms. Nevertheless, it remained challenging to interpret correlations linking the structure and properties of chemical agents to their subcellular localization patterns in large numbers of cells, captured across large number of images.ResultsTo address this challenge, we constructed a Multidimensional Online Virtual Image Display (MOVID) visualization platform using off-the-shelf hardware and software components. For analysis, the image data set acquired from cells incubated with a combinatorial library of fluorescent molecular probes was sorted based on quantitative relationships between the chemical structures, physicochemical properties or predicted subcellular distribution patterns. MOVID enabled visual inspection of the sorted, multidimensional image arrays: Using a multipanel desktop liquid crystal display (LCD) and an avatar as a graphical user interface, the resolution of the images was automatically adjusted to the avatar's distance, allowing the viewer to rapidly navigate through high resolution image arrays, zooming in and out of the images to inspect and annotate individual cells exhibiting interesting staining patterns. In this manner, MOVID facilitated visualization and interpretation of quantitative structure-localization relationship studies. MOVID also facilitated direct, intuitive exploration of the relationship between the chemical structures of the probes and their microscopic, subcellular staining patterns.ConclusionMOVID can provide a practical, graphical user interface and computer-assisted image data visualization platform to facilitate bioimage data mining and cheminformatics analysis of high content, phenotypic screening experiments.

Dataset Information

Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.

Publications

Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.

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