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 journalArticlepeer-review

17 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 languageEnglish
Pages (from-to)961-964
Number of pages4
JournalAngewandte Chemie - International Edition
Volume54
Issue number3
DOIs
StatePublished - Nov 27 2015

Keywords

  • Antitumor agents
  • Fluorescent probe
  • Metabolism
  • Natural products
  • Polyketides

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