Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 6, Pages 2189-2198Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.10.077
Keywords
Wnt signaling; Luciferase; HDAC; Natural product library; LCMS; Bromotyrosine; Psammaplin; N-Methyl glutathione; Disulfide exchange; Reductive methylation; Sulfinate ester
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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. (C) 2008 Elsevier Ltd. All rights reserved.
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