Carteriosulfonic Acids A−C, GSK-3β Inhibitors from a Carteriospongia sp.

Abstract

Modulators of Wnt signaling have therapeutic potential in a number of human diseases. A fractionated library from marine invertebrates was screened in a luciferase assay designed to identify modulators of Wnt signaling. A fraction from a Carteriospongia sp. sponge activated Wnt signaling and was subsequently shown to inhibit GSK-3β, which inhibits Wnt signaling through phosphorylation of β-catenin. Three novel natural products, carteriosulfonic acids A (1), B (2) and C (3), were identified as active constituents. The carteriosulfonic acids contain unprecedented 4,6,7,9-tetrahydroxylated decanoic acid subunits. Their structures were elucidated through analysis of NMR data and a detailed analysis of pseudo MS 3 spectra.The Wnt signaling pathway plays major roles in controlling cell proliferation and differentiation; therefore, misregulation of the Wnt pathway has been implicated in a number of human diseases including cancer and neurodegenerative diseases. 1 The kinase GSK-3β negatively regulates mammalian Wnt signaling via phosphorylation of β-catenin in the destruction complex. Upon phosphorylation of β-catenin by GSK-3β, β-catenin is targeted and ubiquitinated by b-TrCP and subsequently degraded by the proteasome. Activation of Wnt signaling leads to disheveled-mediated inhibition of GSK-3β allowing β-catenin to activate transcription of Wnt/β-catenin responsive genes.We recently outlined a screen to identify modulators of Wnt signaling from a fractionated marine natural products library. Recently, we reported studies on bromotyrosine derivatives that activated the Wnt signaling reporter in a non-specific manner through HDAC inhibition. 2 Herein, we report biological and chemical studies on another hit from the screen. A fraction derived from a Carteriospongia sp. was a Wnt signaling activator and yielded three new low μM inhibitors of GSK-3β, carteriosulfonic acids A (1), B (2) and C (3). These natural products contain an unprecedented 4,6,7,9-tetrahydroxylated decanoic acid subunit that is derivatized as an amide with taurine and further esterified at O-9 with long-chain allylic-alcohol-containing fatty acid groups. The differences between 1, 2 and 3 lie in the long-chain fatty acid components.*Corresponding author. Tel.: +1-801-581-8305; Fax: +1-801-585-6208; cireland@pharm.utah.edu. Supporting Information Available: The following supporting information is available: 1 H NMR spectra of 1-3, 7, 11 and 12; gHMBC spectra of 1-3, and 11; gHSQC spectra of 11 and 12; a 13 C NMR spectrum of 7; and dose response curves for carteriosulfonic acids A, B and C against GSK-3β. This material is available free of charge via the internet at http://pubs.acs.org. Structurally, the carteriosulfonic acids are most closely related to taurospongin A and irciniasulfonic acid B. All of these compounds contain taurine functionalized decanoic acid subunits; however, they differ in the substitution patterns on the decanoic subunits and in the make up of the long chain fatty acid components. Taurospongin A was obtained from a ...

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