PhD defence T. Gül
|When:||Fr 10-02-2017 at 16:15|
Electrochemical and enzymatic synthesis of oxidative drug metabolites for metabolism studies
The thesis of Turan Gül aims to expand the toolbox of electrochemical and enzymatic methods for the selective synthesis of Phase I oxidative metabolites of drug molecules catalyzed by CYP450 and FMO enzymes to produce them in sufficient quantities for the further characterization and toxicity screens. Characterization and identification of drug metabolites was performed using High-Performance Liquid Chromatography coupled to Tandem Mass Spectrometry.
Metabolism studies of drug molecules play a crucial role in drug discovery and development since the early detection of possibly toxic drug metabolites can save time and money. During the metabolic biotransformation process, oxidation of a drug molecule is catalyzed by specific enzymes which can lead to activation or inactivation of the molecule. Phase I metabolism includes primary oxidation reactions including heteroatom dealkylation/oxidation and aromatic hydroxylation reactions which are mainly catalyzed by the cytochrome P450 (CYP450) enzyme family and to a lesser extent by the flavin-containing monooxygenase (FMO) enzyme family.
The use of in vivo and in vitro experimental models, such as whole animal models, liver microsomes and isolated enzymes provides information of drug metabolism in terms of CYP450 and FMO-mediated oxidation reactions; however, they are often not sufficient for preparative scale synthesis. Although organic synthesis methods can overcome this challenge, in most cases severe reaction conditions, hazardous chemicals and multiple reaction steps are required. In this respect, electrochemistry (EC) is an interesting alternative that may be suitable for cleaner and simpler preparative scale synthesis of drug metabolites. In addition, electrochemistry in combination with mass spectrometry (MS) is an emerging instrumental technique to study oxidative drug metabolism in detail.