Chemo-enzymatic Total Syntheses of Jorunnamycin A, Saframycin A, and N-Fmoc Saframycin Y3
| Autor: | Ryo Tanifuji, Ryutaro Asano, Hiroki Oguri, Kento Koketsu, Michiko Takakura, Hideaki Oikawa, Atsushi Minami |
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| Rok vydání: | 2018 |
| Předmět: |
Chemo enzymatic
Quinolones Protein Engineering 010402 general chemistry 01 natural sciences Biochemistry Chemical synthesis Catalysis chemistry.chemical_compound Colloid and Surface Chemistry Biosynthesis Nonribosomal peptide medicine Peptide Synthases chemistry.chemical_classification Aldehydes Antibiotics Antineoplastic Molecular Structure 010405 organic chemistry Tetrahydroisoquinoline General Chemistry Isoquinolines Combinatorial chemistry Recombinant Proteins 0104 chemical sciences Enzyme chemistry Saframycin A THIQ medicine.drug |
| Zdroj: | Journal of the American Chemical Society. 140:10705-10709 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | The antitumor tetrahydroisoquinoline (THIQ) alkaloids share a common pentacyclic scaffold that is biosynthesized by nonribosomal peptide synthetases involving unique enzymatic Pictet-Spengler cyclizations. Herein we report concise and divergent chemo-enzymatic total syntheses of THIQ alkaloids by merging precise chemical synthesis with in vitro engineered biosynthesis. A recombinant enzyme SfmC responsible for the biosynthesis of saframycin A was adapted for the assembly of these natural products and their derivatives, by optimizing designer substrates compatible with SfmC through chemical synthesis. The appropriately functionalized pentacyclic skeleton were efficiently synthesized by streamlining the linkage between SfmC-catalyzed multistep enzymatic conversions and chemical manipulations of the intermediates to install aminonitrile and N-methyl groups. This approach allowed rapid access to the elaborated pentacyclic skeleton in a single day starting from two simple synthetic substrates without isolation of the intermediates. Further functional group manipulations allowed operationally simple and expeditious syntheses of jorunnamycin A, saframycin A, and N-Fmoc saframycin Y3 that could be versatile and common precursors for the artificial production of other antitumor THIQ alkaloids and their variants. |
| Databáze: | OpenAIRE |
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