Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.
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.
McCulloch
Malcolm W B
MW
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Coombs
Gary S
GS
Banerjee
Nikhil
N
Bugni
Tim S
TS
Cannon
Kendell M
KM
Harper
Mary Kay
MK
Veltri
Charles A
CA
Virshup
David M
DM
Ireland
Chris M
CM
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
D004220:Disulfides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C475724:bromotyrosine; C098378:psammaplin A; D014443:Tyrosine