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

Sean M. DeGuire; David C. Earl; Yu Du; Brenda A. Crews; Aaron T. Jacobs; Alessandro Ustione; Cristina Daniel; Katherine M. Chong; Lawrence J. Marnett; David W. Piston; Brian O. Bachmann; Gary A. Sulikowski

doi:10.1002/anie.201408906

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

Sean M. DeGuire, David C. Earl, Yu Du, Brenda A. Crews, Aaron T. Jacobs, Alessandro Ustione, Cristina Daniel, Katherine M. Chong, Lawrence J. Marnett, David W. Piston, Brian O. Bachmann, Gary A. Sulikowski

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 μM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed submicromolar 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.

Original language	English
Pages (from-to)	961-964
Number of pages	4
Journal	Angewandte Chemie - International Edition
Volume	54
Issue number	3
DOIs	https://doi.org/10.1002/anie.201408906
State	Published - Nov 27 2015

Keywords

Antitumor agents
Fluorescent probe
Metabolism
Natural products
Polyketides

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10.1002/anie.201408906

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title = "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 μM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed submicromolar 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.",

keywords = "Antitumor agents, Fluorescent probe, Metabolism, Natural products, Polyketides",

author = "DeGuire, {Sean M.} and Earl, {David C.} and Yu Du and Crews, {Brenda A.} and Jacobs, {Aaron T.} and Alessandro Ustione and Cristina Daniel and Chong, {Katherine M.} and Marnett, {Lawrence J.} and Piston, {David W.} and Bachmann, {Brian O.} and Sulikowski, {Gary A.}",

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year = "2015",

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doi = "10.1002/anie.201408906",

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AU - DeGuire, Sean M.

AU - Earl, David C.

AU - Du, Yu

AU - Crews, Brenda A.

AU - Jacobs, Aaron T.

AU - Ustione, Alessandro

AU - Daniel, Cristina

AU - Chong, Katherine M.

AU - Marnett, Lawrence J.

AU - Piston, David W.

AU - Bachmann, Brian O.

AU - Sulikowski, Gary A.

PY - 2015/11/27

Y1 - 2015/11/27

N2 - 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 submicromolar 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.

AB - 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 submicromolar 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.

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

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