One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases

  • Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2O2-dependent transformation of pharmaceuticals. We have applied UPOs in a drug development program and consider the enzymatic approach in parallel to a conventional chemical synthesis of the human metabolites of the bile acid reabsorption inhibitor SAR548304. Chemical preparation of N,N-di-desmethyl metabolite was realized by a seven-step synthesis starting from a late precursor of SAR548304 and included among others palladium catalysis and laborious chromatographic purification with an overall yield of 27%. The enzymatic approach revealed that the UPO of Marasmius rotula is particularly suitable for selective N-dealkylation of the drug and enabled us to prepare both human metabolites via one-pot conversion with an overall yield of 66% N,N-di-desmethyl metabolite and 49% of N-mono-desmethylated compound in two separated kinetic-controlled reactions.

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Author: Jan Kiebist, Wolfgang Holla, Johannes Heidrich, Marzena Poraj-Kobielska, Martin Sandvoss, Reiner Simonis, Glenn Gröbe, Jens Atzrodt, Martin HofrichterORCiD, Katrin Scheibner
URL:http://www.sciencedirect.com/science/article/pii/S0968089615005295
DOI:https://doi.org/10.1016/j.bmc.2015.06.035
ISSN:0968-0896
Title of the source (English):Bioorganic & Medicinal Chemistry
Document Type:Scientific journal article peer-reviewed
Language:English
Year of publication:2015
Tag:Peroxgenase
Volume/Year:23
Issue number:15
First Page:4324
Last Page:4332
Faculty/Chair:Fakultät 2 Umwelt und Naturwissenschaften / FG Enzymtechnologie
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