Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives

• Published in: Bioorganic & medicinal chemistry 2009-03, Vol.17 (6), p.2189-2198
• Main Authors: McCulloch, Malcolm W.B., Coombs, Gary S., Banerjee, Nikhil, Bugni, Tim S., Cannon, Kendell M., Harper, Mary Kay, Veltri, Charles A., Virshup, David M., Ireland, Chris M.
• Format: Article
• Language: English
• Subjects: Animals; Bromotyrosine; Cell Line; Disulfide exchange; Disulfides - pharmacology; Enzyme Inhibitors - pharmacology; HDAC; Histone Deacetylase Inhibitors; LCMS; Luciferase; Magnetic Resonance Spectroscopy; Metazoa; N-Methyl glutathione; Natural product library; Porifera; Psammaplin; Reductive methylation; Signal Transduction - drug effects; Sulfinate ester; Tyrosine - analogs & derivatives; Tyrosine - chemistry; Tyrosine - pharmacology; Wnt signaling
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.10.077

The Wnt signaling pathway regulates cell growth and development in metazoans, and is therefore of interest for drug discovery. By screening a library of 5808 pre-fractionated marine extracts in a cell-based Wnt signaling assay, several signaling activators and inhibitors were observed. LCMS-based fractionation rapidly identified an active compound from Pseudoceratina purpurea as psammaplin A, a known HDAC inhibitor. Other HDAC inhibitors similarly activated signaling in this assay, indicating HDAC inhibitors will be identified through many cell-based reporter assays. In a large scale analysis of P. purpurea, three previously undescribed bromotyrosine based natural products were identified; the structure of one of these was confirmed by synthesis. Additionally, three other derivatives of psammaplin A were prepared: a mixed disulfide and two sulfinate esters. Finally, evidence to support a structural reassignment of psammaplin I from a sulfone to the isomeric sulfinate ester is presented.