Mechanism of aromatic hydroxylation of lidocaine at a Pt electrode under acidic conditions

Abstract

Please cite this article as: Turan Gül, Rainer Bischoff, Hjalmar P.Permentier, Mechanism of aromatic hydroxylation of lidocaine at a Pt electrode under acidic conditions, Electrochimica Acta http://dx. AbstractAromatic hydroxylation reactions, which are mainly catalyzed by cytochrome P450 (CYP) enzymes in vivo, are some of the most important reactions of Phase I metabolism, because insertion of a hydroxyl group into a lipophilic drug compound increases its hydrophilicity and prepares it for subsequent Phase II metabolic conjugation reactions as a prerequisite to excretion. Aromatic hydroxylation metabolites of pharmaceuticals may be obtained through various synthetic and enzymatic methods. Electrochemical oxidation is an alternative with advantages in terms of mild reaction conditions and less hazardous chemicals. In the present study, we report that aromatic hydroxylation metabolites of lidocaine can be readily obtained electrochemically under aqueous acidic conditions at platinum electrodes. Our results show that the dominant N-dealkylation reaction can be suppressed by decreasing the solution pH below 0.5 resulting in selective 3hydroxylidocaine, which is an in vivo metabolite of lidocaine. Experiments in 18 O labelled water indicated that water is the primary source of oxygen, while dissolved molecular oxygen contributes to a minor extent to the hydroxylation reaction. Key words -Drug metabolism -Aromatic hydroxylation -Pt-oxide layer -Electrochemical synthesis -18 O labeled water

Online Coupling of a Catalytic Continuous Microflow Reactor to Mass Spectrometry

“…The iminium ion intermediate reacts with water via α-carbon hydroxylation (1b), a well-known reaction for enzymatic secondary and tertiary amine oxidations [26], followed by elimination of acetaldehyde (3) producing norlidocaine (2). This mechanism has also been described for electrochemical oxidation reactions, potentially producing additional hydroxylated by-products [27][28][29] that were not detected in our set-up.…”

Metabolism‐Inspired Electrosynthesis

“…Similar methods have been applied to paracetamol by the same group . Gul and colleagues have further optimised the reaction via a design of experiments approach alongside 18 O‐labelling studies to interrogate the mechanism …”

“…[61] Gul and colleagues have further optimised the reaction via a design of experiments approach alongside 18 Olabelling studies to interrogate the mechanism. [62][63] There is a growing body of examples of preparative electrosynthesis to drug metabolites. Could this ability to late stage functionalise (LSF) drug molecules be taken one step further and used to develop metabolism inspired electrosynthetic reactions with the goal to generate drug molecules and metabolites more generally?…”

Electrochemistry of Eugenol and its Metabolism on a Bare Screen-Printed Electrode

“…As a consequence, the need for cheaper and faster alternatives is essential. Considering that the majority of phase I reactions are mainly oxidations (Chadwick and Shaw, 2002;Gul et al, 2017); electrochemistry can provide a suitable method for generating reactive intermediates. The last decade, extensive research has been carried out by Karst research group (Faber et al, 2014;Brauckmann et al, 2013;Baumann et al, 2010;Simon et al, 2016;Frensemeier et al, 2016) towards the electrochemical mimicry of various drugs.…”