Cunninghamella as a Microbiological Model for Metabolism of Histamine H^sub 3^ Receptor Antagonist 1-[3-(4-tert-Butylphenoxy)propyl]piperidine

• Published in: Applied biochemistry and biotechnology 2012-11, Vol.168 (6), p.1584
• Main Authors: Pkala, Elbieta, Kubowicz, Paulina, Aewska, Dorota
• Format: Article
• Language: English
• Subjects: Antagonist drugs; Biosynthesis; Biotechnology; Biotransformation; Carboxylic acids; Histamine; Metabolites; Oxidation; Oxidation process; Pharmaceutical sciences; Xenobiotics
• ISSN: 0273-2289; 1559-0291
• DOI: 10.1007/s12010-012-9880-8

The aim of the study was to analyze the ability of the microorganism Cunninghamella to carry out the biotransformation of 1-[3-(4-tert-butylphenoxy)propyl]piperidine (DL76) and to compare the obtained results with in silico models. Biotransformation was carried out by three strains of filamentous fungus: Cunninghamella echinulata, Cunninghamella blakesleeana, and Cunninghamella elegans. Most probable direction of DL76 metabolic transition was the oxidation of the methyl group in the tert-butyl moiety leading to the formation of the metabolite with I° alcohol properties. This kind of reaction was conducted by all three strains tested. However, only in the case of C. blakesleeana that biotransformation product had a structure of carboxylic acid. CYP2C19 was identified by Metasite software to be the isoform of major importance in the oxidation process in the tert-butyl moiety of DL76. In silico data coincide with the results of experiments conducted in vitro. It was confirmed that Cunninghamella fungi are a very good model to study the metabolism of xenobiotics. The computational methods and microbial models of metabolism can be used as useful tools in early ADME-Tox assays in the process of developing new drug candidates.[PUBLICATION ABSTRACT]