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

DeGuire SM, Earl DC, Du Y, Crews BA, Jacobs AT, Ustione A, Daniel C, Chong KM, Marnett LJ, Piston DW, Bachmann BO, Sulikowski GA
Angew Chem Int Ed Engl. 2015 54 (3): 961-4

PMID: 25430909 · PMCID: PMC4293314 · DOI:10.1002/anie.201408906

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 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.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

MeSH Terms (9)

Antineoplastic Agents Apoptosis Cell Line, Tumor Fluorescent Dyes Humans Lipid Peroxidation Macrolides Microscopy, Confocal Pyrones

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