title: One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.
abstract: 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.
authors.affiliation: Enzymtechnology, Faculty of Science, BTU Cottbus-Senftenberg, Großenhainer Str. 57, 01968 Senftenberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kiebist
authors.affiliation: Isotope Chemistry & Metabolite Synthesis, DSAR-DD, Sanofi-Aventis, Industriepark Höchst G876, 65926 Frankfurt am Main, Germany. Electronic address: Wolfgang.Holla@sanofi.com.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holla
authors.affiliation: Isotope Chemistry & Metabolite Synthesis, DSAR-DD, Sanofi-Aventis, Industriepark Höchst G876, 65926 Frankfurt am Main, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Heidrich
authors.affiliation: Department of Bio- and Environmental Sciences, TU Dresden-IHI Zittau, Markt 23, 02763 Zittau, Germany.
authors.forename: Marzena
authors.initials: M
authors.lastname: Poraj-Kobielska
authors.affiliation: Isotope Chemistry & Metabolite Synthesis, DSAR-DD, Sanofi-Aventis, Industriepark Höchst G876, 65926 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sandvoss
authors.affiliation: Isotope Chemistry & Metabolite Synthesis, DSAR-DD, Sanofi-Aventis, Industriepark Höchst G876, 65926 Frankfurt am Main, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Simonis
authors.affiliation: Enzymtechnology, Faculty of Science, BTU Cottbus-Senftenberg, Großenhainer Str. 57, 01968 Senftenberg, Germany.
authors.forename: Glenn
authors.initials: G
authors.lastname: Gröbe
authors.affiliation: Isotope Chemistry & Metabolite Synthesis, DSAR-DD, Sanofi-Aventis, Industriepark Höchst G876, 65926 Frankfurt am Main, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Atzrodt
authors.affiliation: Department of Bio- and Environmental Sciences, TU Dresden-IHI Zittau, Markt 23, 02763 Zittau, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hofrichter
authors.affiliation: Enzymtechnology, Faculty of Science, BTU Cottbus-Senftenberg, Großenhainer Str. 57, 01968 Senftenberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Scheibner
mesh_terms: D002384:Catalysis; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D055433:Marasmius / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010165:Palladium / Q000737:chemistry; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D006571:Heterocyclic Compounds; D010671:Phenylurea Compounds; C000607518:SAR548304; D010165:Palladium; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; C022333:peroxygenase; D005944:Glucosamine
keywords: Drug metabolite synthesis; EC 1.11.2.1; N-dealkylation; UPO; Unspecific peroxygenase