One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Kiebist, Jan; Holla, Wolfgang; Heidrich, Johannes; Poraj-Kobielska, Marzena; Sandvoss, Martin; Simonis, Reiner; Gröbe, Glenn; Atzrodt, Jens; Hofrichter, Martin; Scheibner, Katrin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 4324
• Page End: 4332
• Publication Date: 2015-08-01
• Subjects: Drug metabolite synthesis -- Unspecific peroxygenase -- UPO -- EC 1.11.2.1 -- N-dealkylation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.035
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2 O2 -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.