Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6805-10. doi: 10.1073/pnas.1015269108. Epub 2011 Mar 17.
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).
在生物导向合成中，生物相关化合物类别的支架激发了具有生物活性的聚焦化合物集合的合成。这一标准符合在进化中选择的天然产物 (NPs) 的结构复杂支架。为了合成接近 NPs 复杂性的 NP 启发的化合物集合，需要开发有效的合成方法。我们开发了一种一锅法 4-7 步合成单环、双环和三环氧杂环戊烷的方法，这些化合物类似于具有多种生物活性的许多 NPs 的核心支架。该序列需要作为关键步骤的闭环烯炔复分解反应，并有效地利用聚合物固定的清除试剂。在监测 Wnt 信号调节的报告基因测定中，对相应聚焦化合物集合进行的生物学特征分析显示出活性的 Wntepanes。这种独特的小分子 Wnt 途径激活剂类调节以前在非典型 Wnt 信号中发现的梵高样受体蛋白 (Vangl)，并与典型的激活蛋白 (Wnt-3a) 协同作用。
