Regioselective preparation of 5-hydroxypropranolol and 4'-hydroxydiclofenac with a fungal peroxygenase.
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.
Kinne
Matthias
M
Unit of Environmental Biotechnology, International Graduate School of Zittau, Zittau, Germany. barbara_attenni@merck.com
Poraj-Kobielska
Marzena
M
Aranda
Elisabet
E
Ullrich
René
R
Hammel
Kenneth E
KE
Scheibner
Katrin
K
Hofrichter
Martin
M
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
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