Preparation of labeled human drug metabolites and drug-drug interaction-probes with fungal peroxygenases

  • Enzymatic conversion of a drug can be an efficient alternative for the preparation of a complex metabolite compared with a multi-step chemical synthesis approach. Limitations exist for chemical methods for direct oxygen incorporation into organic molecules often suffering from low yields and unspecific oxidation and also for alternative whole-cell biotransformation processes, which require specific fermentation know-how. Stable oxygen-transferring biocatalysts such as unspecific peroxygenases (UPOs) could be an alternative for the synthesis of human drug metabolites and related stable isotope-labeled analogues. This work shows that UPOs can be used in combination with hydrogen/deuterium exchange for an efficient one-step process for the preparation of 4'-OH-diclofenac-d6. The scope of the reaction was investigated by screening of different peroxygenase subtypes for the transformation of selected deuterium-labeled substrates such as phenacetin-d3 or lidocaine-d3. Experiments with diclofenac-d7 revealed that the deuterium-labeling doesEnzymatic conversion of a drug can be an efficient alternative for the preparation of a complex metabolite compared with a multi-step chemical synthesis approach. Limitations exist for chemical methods for direct oxygen incorporation into organic molecules often suffering from low yields and unspecific oxidation and also for alternative whole-cell biotransformation processes, which require specific fermentation know-how. Stable oxygen-transferring biocatalysts such as unspecific peroxygenases (UPOs) could be an alternative for the synthesis of human drug metabolites and related stable isotope-labeled analogues. This work shows that UPOs can be used in combination with hydrogen/deuterium exchange for an efficient one-step process for the preparation of 4'-OH-diclofenac-d6. The scope of the reaction was investigated by screening of different peroxygenase subtypes for the transformation of selected deuterium-labeled substrates such as phenacetin-d3 or lidocaine-d3. Experiments with diclofenac-d7 revealed that the deuterium-labeling does not affect the kinetic parameters. By using the latter substrate and H2 (18) O2 as cosubstrate, it was possible to prepare a doubly isotope-labeled metabolite (4'-(18) OH-diclofenac-d6). UPOs offer certain practical advantages compared with P450 enzyme systems in terms of stability and ease of handling. Given these advantages, future work will expand the existing 'monooxygenation toolbox' of different fungal peroxygenases that mimic P450 in vitro reactions.show moreshow less

Export metadata

Additional Services

Search Google Scholar
Metadaten
Author: Marzena Poraj-Kobielska, Jens Atzrodt, Wolfgang Holla, Martin Sandvoss, Glenn Gröbe, Katrin Scheibner, Martin HofrichterORCiD
URL:http://onlinelibrary.wiley.com/doi/10.1002/jlcr.3103/abstract;jsessionid=5453A37788468921BE8A03CABF2928DD.f03t02
DOI:https://doi.org/10.1002/jlcr.3103
ISSN:1099-1344
Title of the source (English):Journal of Labelled Compounds and Radiopharmaceuticals
Document Type:Scientific journal article peer-reviewed
Language:English
Year of publication:2013
Tag:4'OH-diclofenac; EC 1.11.2.1;; Isotopic labeled synthesis; deuterium; human drug metabolites; lidocaine; paracetamol; phenacetin; unspecific/aromatic peroxygenase
Volume/Year:56
Issue number:9-10
First Page:513
Last Page:519
Faculty/Chair:Fakultät 2 Umwelt und Naturwissenschaften / FG Enzymtechnologie
Institution name at the time of publication:Fakultät für Naturwissenschaften (eHL) / Prof. Enzymtechnologie
Einverstanden ✔
Diese Webseite verwendet technisch erforderliche Session-Cookies. Durch die weitere Nutzung der Webseite stimmen Sie diesem zu. Unsere Datenschutzerklärung finden Sie hier.