title: Biology-oriented synthesis of a natural-product inspired oxepane collection yields a small-molecule activator of the Wnt-pathway.
abstract: In Biology Oriented Synthesis the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is met by the structurally complex scaffolds of natural products (NPs) selected in evolution. The synthesis of NP-inspired compound collections approaching the complexity of NPs calls for the development of efficient synthetic methods. We have developed a one pot 4-7 step synthesis of mono-, bi-, and tricyclic oxepanes that resemble the core scaffolds of numerous NPs with diverse bioactivities. This sequence entails a ring-closing ene-yne metathesis reaction as key step and makes productive use of polymer-immobilized scavenger reagents. Biological profiling of a corresponding focused compound collection in a reporter gene assay monitoring for Wnt-signaling modulation revealed active Wntepanes. This unique class of small-molecule activators of the Wnt pathway modulates the van-Gogh-like receptor proteins (Vangl), which were previously identified in noncanonical Wnt signaling, and acts in synergy with the canonical activator protein (Wnt-3a).
authors.affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ellinger
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizzo
authors.forename: Céline
authors.initials: C
authors.lastname: Deraeve
authors.forename: Markus
authors.initials: M
authors.lastname: Schürmann
authors.forename: Hans
authors.initials: H
authors.lastname: Preut
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Arndt
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D002352:Carrier Proteins; D006571:Heterocyclic Compounds; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein