Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone. Issue 67 (13th October 2022)

• Record Type: Journal Article
• Authors: Grigalunas, Michael; Patil, Sohan; Krzyzanowski, Adrian; Pahl, Axel; Flegel, Jana; Schölermann, Beate; Xie, Jianing; Sievers, Sonja; Ziegler, Slava; Waldmann, Herbert
• Is Part Of: Chemistry. Volume 28:Issue 67(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-13
• Subjects: chemical evolution -- griseofulvin -- hedgehog signaling inhibitors -- polyketide natural product fragments -- pseudo-natural products; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202202164
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : The chemical evolution of polyketide natural products leads to the unprecedented combination of biosynthetically related fragments in arrangements not found in Nature. The pseudo‐natural product grismonone was identified to be a potent inhibitor of Hedgehog signaling – a bioactivity that is not shared by its guiding fragments.