Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, 44227, Germany.
Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Dortmund, 44227, Germany.
Chemistry. 2022 Dec 1;28(67):e202202164. doi: 10.1002/chem.202202164. Epub 2022 Oct 13.
Pseudo-natural products (pseudo-NPs) are de novo combinations of natural product (NP) fragments that define novel bioactive chemotypes. For their discovery, new design principles are being sought. Previously, pseudo-NPs were synthesized by the combination of fragments originating from biosynthetically unrelated NPs to guarantee structural novelty and novel bioactivity. We report the combination of fragments from biosynthetically related NPs in novel arrangements to yield a novel chemotype with activity not shared by the guiding fragments. We describe the synthesis of the polyketide pseudo-NP grismonone and identify it as a structurally novel and potent inhibitor of Hedgehog signaling. The insight that the de novo combination of fragments derived from biosynthetically related NPs may also yield new biologically relevant compound classes with unexpected bioactivity may be considered a chemical extension or diversion of existing biosynthetic pathways and greatly expands the opportunities for exploration of biologically relevant chemical space by means of the pseudo-NP principle.
伪天然产物（pseudo-NPs）是天然产物（NP）片段的从头组合，定义了新型的生物活性化学型。为了发现它们，人们正在寻找新的设计原则。以前，通过将来自生物合成上无关的 NPs 的片段组合来合成伪 NPs，以保证结构新颖性和新的生物活性。我们报告了在新的排列中组合来自生物合成上相关的 NPs 的片段，以产生一种具有指导片段所不具有的活性的新型化学型。我们描述了多酮伪 NP grismonone 的合成，并将其鉴定为 Hedgehog 信号的结构新颖且强效抑制剂。从生物合成上相关的 NPs 衍生的片段的从头组合也可能产生具有意外生物活性的新型生物相关化合物类别的这一见解，可以被认为是现有生物合成途径的化学延伸或分支，极大地扩展了通过伪 NP 原理探索生物相关化学空间的机会。
