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Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

ABSTRACT: Apoptolidin?A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin?A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin?A, the aglycone (apoptolidinone) shows no cytotoxicity (>10??M) when evaluated against several tumor cell lines. Apoptolidin?H, the C27 deglycosylated analogue of apoptolidin?A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidins?A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidins?A and H localize in the mitochondria of H292 human lung carcinoma cells.

SUBMITTER: DeGuire SM

PROVIDER: S-EPMC4293314 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

DeGuire Sean M SM Earl David C DC Du Yu Y Crews Brenda A BA Jacobs Aaron T AT Ustione Alessandro A Daniel Cristina C Chong Katherine M KM Marnett Lawrence J LJ Piston David W DW Bachmann Brian O BO Sulikowski Gary A GA

Angewandte Chemie (International ed. in English) 20141127 3

Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 μM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed sub-micromolar activity against H2 ...[more]

PMID: 25430909

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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

Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

Publications

Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

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