Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone

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.

Collective Synthesis of Sarpagine and Macroline Alkaloid‐Inspired Compounds

“…The hydantoin fragment, [18] which is found in neither Macroline nor Sarpagine NPs, was selected for combination with 4 to afford pseudo-NP scaffold 5 (Class B). It should be noted that ring fusion to a NP or NP-like scaffold is a design strategy in both pseudo-NP [19,20] and complexity-to-diversity principles. [3,21] A rearrangement of the core indole and [3.3.1]homotropane fragments of Macroline and Sarpagine NPs was envisioned via an intramolecular N-acylation reaction of divergent intermediate 3 to afford pseudo NPs 6 (Class C).…”

Exploring the Potential of Anthraquinone‐Based Hybrids for Identifying a Novel Generation of Antagonists for the Smoothened Receptor in HH‐Dependent Tumour

“…Indeed, many of the HH inhibitors occur in nature or derive from NPs by means of chemical transformations or total syntheses, which further emphasizes the renewed interest in nature as a source of “hit and lead” compounds in drug discovery [20] . Different design strategies have been utilized to achieve unprecedented and intriguing architectures by intelligently manipulating the NP′s core‐scaffold [21–27] …”

“…[20] Different design strategies have been utilized to achieve unprecedented and intriguing architectures by intelligently manipulating the NP's corescaffold. [21][22][23][24][25][26][27] In this context, an alternative approach to discover new biologically relevant compounds, by exploiting the biologically relevant chemical space of NPs, starts from natural chemotypes and employs the combination of the basic skeleton of a NP with a molecularly targeted drug bullet. [28,29] Among the different classes of natural products, anthraquinones, which are secondary metabolites widely distributed in higher plants (aloe, cascara sagrada, senna and rhubarb), microorganisms, lichens and insects, display a wide variability of biological effects.…”

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

“…[7][8][9] According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP-like but are not accessible via known biosynthetic pathways. The pseudo-NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10][11][12] or unprecedented bioactivities. [13] We describe the design and synthesis of a focused pseudo-NP collection comprised of two classes representing unprecedented scaffolds that occupy similar biologically relevant chemical space as MIA NPs (Figure 1b).…”

“…According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP‐like but are not accessible via known biosynthetic pathways. The pseudo‐NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10–12] or unprecedented bioactivities [13] …”