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Fluorescent Probes of the Apoptolidins and their Utility in Cellular Localization Studies
Author(s) -
DeGuire Sean M.,
Earl David C.,
Du Yu,
Crews Brenda A.,
Jacobs Aaron T.,
Ustione Alessandro,
Daniel Cristina,
Chong Katherine M.,
Marnett Lawrence J.,
Piston David W.,
Bachmann Brian O.,
Sulikowski Gary A.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201408906
Subject(s) - cytotoxicity , fluorescence , chemistry , cell culture , cycloaddition , aglycone , stereochemistry , alkyne , cytotoxic t cell , fluorescence microscope , biochemistry , biology , in vitro , physics , quantum mechanics , glycoside , genetics , catalysis
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 μ 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.