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 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.
authors.affiliation: Department of Chemistry, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232 (USA).
authors.forename: Sean M
authors.initials: SM
authors.lastname: DeGuire
authors.forename: David C
authors.initials: DC
authors.lastname: Earl
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Crews
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Jacobs
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ustione
authors.forename: Cristina
authors.initials: C
authors.lastname: Daniel
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Chong
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bachmann
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D018942:Macrolides / Q000737:chemistry* / Q000633:toxicity; D018613:Microscopy, Confocal; D011753:Pyrones / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D018942:Macrolides; D011753:Pyrones; C506738:apoptolidin A; C114125:apoptolidin
keywords: antitumor agents; fluorescent probe; metabolism; natural products; polyketides