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, 17 (6), 2189-98

Psammaplin A as a General Activator of Cell-Based Signaling Assays via HDAC Inhibition and Studies on Some Bromotyrosine Derivatives

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Psammaplin A as a General Activator of Cell-Based Signaling Assays via HDAC Inhibition and Studies on Some Bromotyrosine Derivatives

Malcolm W B McCulloch et al. Bioorg Med Chem.

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.

Figures

Figure 1
Figure 1
Wnt signaling activators identified from the library screen.
Figure 2
Figure 2
Psammaplin A monomeric subunit.
Figure 3
Figure 3
Selected gHMBC correlations (600 MHz) observed for 3.
Figure 4
Figure 4
Selected MSMS fragments for 3.
Figure 5
Figure 5
FT-MSMS of sulfinate ester 6 showed a loss of methanol.
Scheme 1
Scheme 1
Semi-synthesis of 5. Conditions: DTT, K2CO3, THF/MeOH/PBS (pH=8.4), 22 hr, 46% from 1 (unoptimized).
Scheme 2
Scheme 2
Reductive alkylation reactions. Conditions: (a) NaOH (2.1 equiv), 2-nitrobenzaldehdyde (2.2 equiv.), MeOH/H2O, overnight, 83%; (b) NaBH3CN, ACN/DMSO, AcOH(cat), 3-16 hr, 13 71%; (c) paraformaldehyde (excess), ACN/DMSO, 8-16 hr, (d) NaBH3CN, AcOH(cat), overnight, 12 66-84%, 14 6%.
Scheme 3
Scheme 3
Photolysis of 12 and the semi-synthesis of 3. Conditions: (a) 0.5 mmol in ACN, hν 360 nm, 2 hr, 91%; (b) LiOH (5.1 equiv), THF/H2O, overnight; (c) PBS (pH 8.4), MeOH, 1 (6 equiv), DTT, overnight, 38% over two steps.
Scheme 4
Scheme 4
Oxidative methanolysis of 1. Conditions: NBS (2.4 equiv), MeOH, 0°C → room temp., 40 min, 6 11%, 7 14% (unoptimized).

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