Regioselective preparation of 5-hydroxypropranolol and 4′-hydroxydiclofenac with a fungal peroxygenase
- An extracellular peroxygenase of Agrocybe aegerita catalyzed the H2O2-dependent hydroxylation of the multi-function beta-adrenergic blocker propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol) and the non-steroidal anti-inflammatory drug diclofenac (2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid) to give the human drug metabolites 5-hydroxypropranolol (5-OHP) and 4′-hydroxydiclofenac (4′-OHD). The reactions proceeded regioselectively with high isomeric purity and gave the desired 5-OHP and 4′-OHD in yields up to 20% and 65%, respectively. 18O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4′-OHD originated from H2O2, which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of drug metabolites.
Author: | Matthias Kinne, Marzena Poraj-Kobielska, Elisabet Aranda, René UllrichORCiD, Kenneth E. Hammel, Katrin Scheibner, Martin HofrichterORCiD |
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URL: | http://www.sciencedirect.com/science/article/pii/S0960894X09005071 |
DOI: | https://doi.org/10.1016/j.bmcl.2009.04.015 |
ISSN: | 1464-3405 |
Title of the source (English): | Bioorganic & Medicinal Chemistry Letters |
Document Type: | Scientific journal article peer-reviewed |
Language: | English |
Year of publication: | 2009 |
Tag: | 4′-Hydroxydiclofenac; 5-Hydroxypropranolol; Ascorbic acid; Cytochrome P450; Diclofenac; Hydroxylation; Oxygenase; Peroxidase; Peroxygenase; Propranolol |
Volume/Year: | 19 |
Issue number: | 11 |
First Page: | 3085 |
Last Page: | 3087 |
Faculty/Chair: | Fakultät 2 Umwelt und Naturwissenschaften / FG Enzymtechnologie |
Institution name at the time of publication: | Fakultät für Naturwissenschaften (eHL) / Prof. Enzymtechnologie |