One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases
| Autor: | Glenn Gröbe, Marzena Poraj-Kobielska, Katrin Scheibner, Johannes Heidrich, Wolfgang Holla, Reiner Simonis, Martin Hofrichter, Jens Atzrodt, Jan Kiebist, Martin Sandvoss |
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| Rok vydání: | 2015 |
| Předmět: |
Metabolite
Clinical Biochemistry One-pot synthesis Pharmaceutical Science Biochemistry Chemical synthesis Catalysis Mixed Function Oxygenases chemistry.chemical_compound Unspecific peroxygenase Heterocyclic Compounds Drug Discovery Organic chemistry Humans Molecular Biology chemistry.chemical_classification Glucosamine Phenylurea Compounds Organic Chemistry Hydrogen Peroxide Marasmius Enzyme Drug development chemistry Yield (chemistry) Molecular Medicine Palladium |
| Zdroj: | Bioorganicmedicinal chemistry. 23(15) |
| ISSN: | 1464-3391 |
| Popis: | Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2O2-dependent transformation of pharmaceuticals. We have applied UPOs in a drug development program and consider the enzymatic approach in parallel to a conventional chemical synthesis of the human metabolites of the bile acid reabsorption inhibitor SAR548304. Chemical preparation of N,N-di-desmethyl metabolite was realized by a seven-step synthesis starting from a late precursor of SAR548304 and included among others palladium catalysis and laborious chromatographic purification with an overall yield of 27%. The enzymatic approach revealed that the UPO of Marasmius rotula is particularly suitable for selective N-dealkylation of the drug and enabled us to prepare both human metabolites via one-pot conversion with an overall yield of 66% N,N-di-desmethyl metabolite and 49% of N-mono-desmethylated compound in two separated kinetic-controlled reactions. |
| Databáze: | OpenAIRE |
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