Pseudo Natural Products—Chemical Evolution of Natural Product Structure

Karageorgis, George; Foley, Daniel J.; Laraia, Luca; Brakmann, Susanne; Waldmann, Herbert

doi:10.1002/ange.202016575

Cited by 20 publications

(9 citation statements)

References 90 publications

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“…These limitations can be overcome by the design and synthesis of "pseudo-natural products" (pseudo-NPs). [3] In the pseudo-NP concept, NP fragments that represent NP structure and properties [4] are combined through de novo combination to afford unprecedented NP-inspired compound classes not accessible by known biosynthesis pathways. Pseudo-NPs inherit characteristic NP structures and properties but go beyond the chemical space explored by nature and, therefore, promise to have unexpected bioactivity and targets.…”

Section: Introductionmentioning

confidence: 99%

The Pseudo‐Natural Product Rhonin Targets RHOGDI

et al. 2022

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For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment‐based design. We describe the de novo combination of different 5‐membered NP‐derived N‐heteroatom fragments to structurally unprecedented “pseudo‐natural products” in an efficient complexity‐generating and enantioselective one‐pot synthesis sequence. The pseudo‐NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP‐derived chemotypes, and may have novel biological targets. Investigation of the pseudo‐NPs in unbiased phenotypic assays and target identification led to the discovery of the first small‐molecule ligand of the RHO GDP‐dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP‐bound RHO GTPases and alters the subcellular localization of RHO GTPases.

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Section: Introductionmentioning

confidence: 99%

The Pseudo‐Natural Product Rhonin Targets RHOGDI

et al. 2022

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“…Successfully, a nitrogen‐5‐membered ring fused to the 1,4‐benzoquinone system, compound II (indolequinone, Figure 1), exhibited good potency against tropical parasite Trypanosoma cruzi (IC 50 =20.0 nM and SI=625) [13] . Recently, a valuable strategy to identify new useful scaffolds, is the use of natural product‐derived fragments [15,16] . In this context, it was found that 2‐phenylbenzofuran scaffold is constituent of the structure of several bioactive natural products and has been used as a synthetic key intermediate for the construction of several biologically important compounds [17] .…”

Section: Introductionmentioning

confidence: 99%

Phenoxy‐ and Phenylamino‐Heterocyclic Quinones: Synthesis and Preliminary Anti‐Pancreatic Cancer Activity

Sánchez

Salas

Gallardo-Fuentes

et al. 2022

Chemistry & Biodiversity

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The successful application of fragment‐based drug discovery strategy for the efficient synthesis of phenoxy‐ or phenylamino‐2‐phenyl‐benzofuran, ‐benzoxazole and ‐benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated in vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA‐PaCa‐2, BxPC‐3, and AsPC‐1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC‐3 cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA‐PaCa‐2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.

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“…This relevance calls for new approaches in order to discover compound classes that can be considered NP-inspired, but occupy unexplored areas of natural product-like chemical space. The recently introduced pseudo-natural product (PNP) approach [2] combines natural product fragments de novo and through different arrangements to yield compound classes that structurally resemble NPs but are not found in nature. [3] As a result, pseudo-NPs inherit typical properties of NPs from their respective NP fragments, [4] yet occupy biologically relevant chemical space not covered by existing NPs.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

et al. 2022

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Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole-and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

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Pseudo Natural Products—Chemical Evolution of Natural Product Structure

Cited by 20 publications

References 90 publications

The Pseudo‐Natural Product Rhonin Targets RHOGDI

The Pseudo‐Natural Product Rhonin Targets RHOGDI

Phenoxy‐ and Phenylamino‐Heterocyclic Quinones: Synthesis and Preliminary Anti‐Pancreatic Cancer Activity

Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

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