Regioselective preparation of 5-hydroxypropranolol and 4'-hydroxydiclofenac with a fungal peroxygenase

Bioorg Med Chem Lett. 2009 Jun 1;19(11):3085-7. doi: 10.1016/j.bmcl.2009.04.015. Epub 2009 Apr 9.

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.

MeSH terms

  • Agrocybe / enzymology
  • Biocatalysis
  • Cytochrome P-450 Enzyme System / metabolism
  • Diclofenac / analogs & derivatives*
  • Diclofenac / chemistry
  • Hydrogen Peroxide / metabolism
  • Mixed Function Oxygenases / metabolism*
  • Propranolol / analogs & derivatives*
  • Propranolol / chemistry*
  • Propranolol / metabolism
  • Stereoisomerism

Substances

  • 5-hydroxypropranolol
  • Diclofenac
  • Cytochrome P-450 Enzyme System
  • Propranolol
  • Hydrogen Peroxide
  • Mixed Function Oxygenases
  • peroxygenase
  • 4'-hydroxydiclofenac