title: Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Malcolm W B
authors.initials: MW
authors.lastname: McCulloch
authors.forename: Gary S
authors.initials: GS
authors.lastname: Coombs
authors.forename: Nikhil
authors.initials: N
authors.lastname: Banerjee
authors.forename: Tim S
authors.initials: TS
authors.lastname: Bugni
authors.forename: Kendell M
authors.initials: KM
authors.lastname: Cannon
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Harper
authors.forename: Charles A
authors.initials: CA
authors.lastname: Veltri
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.forename: Chris M
authors.initials: CM
authors.lastname: Ireland
mesh_terms: D000818:Animals; D002460:Cell Line; D004220:Disulfides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D011161:Porifera; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004220:Disulfides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C475724:bromotyrosine; C098378:psammaplin A; D014443:Tyrosine