Synthesis of novel inhibitors blocking Wnt signaling downstream of β‐Catenin

Abstract

a b s t r a c tLarge scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/b-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy-and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/b-Catenin signaling.

Formaldehyde‐Extruding Homolytic Aromatic Substitution via C→O Transposition: Selective ‘Traceless‐Linker’ access to Congested Biaryl Bonds

“…During optimisation of the “acetal method” part of the investigations of the BHAS reaction,,—two of us reported the isolation of 2‐phenylphenol ( 7 ) as a by‐product . The procedure employed a molecular tether placed in sequence to form heterodimers with 2‐bromophenol resulting in a methylene bridge and the namesake acetal.…”

Quorum-Sensing Regulation of Antimicrobial Resistance in Bacteria

“…Therefore, many researchers have used artificial synthesis to synthesize quorum-sensing signal analogs to antagonize the quorum-sensing signal of pathogenic bacteria and have achieved certain results [135]. Five different haloquinone analogs were tested carrying different positions of methoxy and hydroxyl [119]. Tests of Wnt activity in cell culture and Xenopus embryos have shown that two of these compounds can be effective inhibitors of abnormally activated Wnt/β-catenin signaling.…”

Optimization of Peptidomimetics as Selective Inhibitors for the β-Catenin/T-Cell Factor Protein–Protein Interaction

“…Extensive efforts have been made to identify several small-molecule inhibitors for this PPI. − However, the binding mode of these compounds remains unknown, making it difficult for further optimization . The large peptides or peptide-based macrocycles have also been designed as β-catenin/Tcf inhibitors. − Hydrocarbon-stapled peptide, aStAx-35, designed based on the Axin sequence and the phage display result, was reported to bind with the Axin-binding site of β-catenin and inhibit the β-catenin/Tcf PPI .…”