Synthesis and Biological Evaluation of Fluorescent Bryostatin Analogues

To investigate the cellular distribution of tumor‐promoting vs. non‐tumor‐promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester‐like or bryostatin‐like biological activity in U937 leukemia cells. Th...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2018-04, Vol.19 (8), p.877-889
Main Authors: Cummins, Thomas J., Kedei, Noemi, Czikora, Agnes, Lewin, Nancy E., Kirk, Sharon, Petersen, Mark E., McGowan, Kevin M., Chen, Jin‐Qiu, Luo, Xiaoling, Johnson, Randall C., Ravichandran, Sarangan, Blumberg, Peter M., Keck, Gary E.
Format: Article
Language:English
Subjects:
Biological activity
bryostatin
Bryostatins - chemistry
Chemical compounds
Fluorescence
Fluorescent Dyes - chemistry
fluorescent probes
Humans
Intracellular
Kinases
Leukemia
Merle
Phorbol Esters - chemistry
Protein Binding
Protein kinase C
Protein Kinase C - metabolism
pyran annulation
Tumors
U937 Cells
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Summary:To investigate the cellular distribution of tumor‐promoting vs. non‐tumor‐promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester‐like or bryostatin‐like biological activity in U937 leukemia cells. These new fluorescent analogues both displayed high affinity for protein kinase C (PKC) binding and retained the basic properties of the parent unlabeled compounds in U937 assays. The fluorescent compounds showed similar patterns of intracellular distribution in cells, however; this argues against an existing hypothesis that various patterns of intracellular distribution are responsible for differences in biological activity. Upon further characterization, the fluorescent compounds revealed a slow rate of cellular uptake; correspondingly, they showed reduced activity for cellular responses that were only transient upon treatment with phorbol ester or bryostatin 1. Bryostatin brightness: To investigate the cellular distribution of tumor‐promoting versus non‐tumor‐promoting bryostatin (Bryo) analogues, we synthesized fluorescent variants of two bryostatin derivatives that had previously shown either phorbol ester‐like or bryostatin 1‐like biological activity in U937 leukemia cells. The compounds had different biology despite their similar subcellular localization.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201700655