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Fluorescent Probes of the Apoptolidins and their Utility in Cellular Localization Studies |
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| Authors: | Dr Sean M DeGuire David C Earl Dr Yu Du Brenda A Crews Dr Aaron T Jacobs Dr Alessandro Ustione Cristina Daniel Katherine M Chong Prof Lawrence J Marnett Prof David W Piston Prof Brian O Bachmann Prof Gary A Sulikowski |
| Institution: | 1. Department of Chemistry, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232 (USA);2. Departments of Biochemistry and Chemistry, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232 (USA);3. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232 (USA) |
| 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. |
| Keywords: | antitumor agents fluorescent probe metabolism natural products polyketides |