title: Regioselective preparation of 5-hydroxypropranolol and 4'-hydroxydiclofenac with a fungal peroxygenase.
abstract: An extracellular peroxygenase of Agrocybe aegerita catalyzed the H(2)O(2)-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. (18)O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4'-OHD originated from H(2)O(2), 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.
authors.affiliation: Unit of Environmental Biotechnology, International Graduate School of Zittau, Zittau, Germany. barbara_attenni@merck.com
authors.forename: Matthias
authors.initials: M
authors.lastname: Kinne
authors.forename: Marzena
authors.initials: M
authors.lastname: Poraj-Kobielska
authors.forename: Elisabet
authors.initials: E
authors.lastname: Aranda
authors.forename: René
authors.initials: R
authors.lastname: Ullrich
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hammel
authors.forename: Katrin
authors.initials: K
authors.lastname: Scheibner
authors.forename: Martin
authors.initials: M
authors.lastname: Hofrichter
mesh_terms: D055362:Agrocybe / Q000201:enzymology; D055162:Biocatalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C542024:5-hydroxypropranolol; D004008:Diclofenac; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; C022333:peroxygenase; C108036:4'-hydroxydiclofenac