Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores
| Autor: | Christian R. Zwick, Max B. Sosa, Hans Renata |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Longest linear sequence
Hydroxylation 010402 general chemistry 01 natural sciences Biochemistry Article Catalysis Mixed Function Oxygenases chemistry.chemical_compound Colloid and Surface Chemistry Natural product business.industry Total synthesis General Chemistry Modular design Combinatorial chemistry Chemical space Anti-Bacterial Agents 0104 chemical sciences Analogue synthesis chemistry Biocatalysis Key (cryptography) Pharmacophore business Oligopeptides |
| Zdroj: | J Am Chem Soc |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space. |
| Databáze: | OpenAIRE |
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