Charged Tags for the Identification of Oxidative Drug Metabolites Based on Electrochemistry and Mass Spectrometry

Abstract

Most of the active pharmaceutical ingredients like Metoprolol are oxidatively metabolized by liver enzymes, such as Cytochrome P450 monooxygenases into oxygenates and therefore hydrophilic products. It is of utmost importance to identify the metabolites and to gain knowledge on their toxic impacts. By using electrochemistry, it is possible to mimic enzymatic transformations and to identify metabolic hot spots. By introducing charged‐tags into the intermediate, it is possible to detect and isolate metabolic products. The identification and synthesis of initially oxidized metabolites are important to understand possible toxic activities. The gained knowledge about the metabolism will simplify interpretation and predictions of metabolitic pathways. The oxidized products were analyzed with high performance liquid chromatography‐mass spectrometry using electrospray ionization (HPLC‐ESI‐MS) and nuclear magnetic resonance (NMR) spectroscopy. For proof‐of‐principle, we present a synthesis of one pyridinated main oxidation product of Metoprolol.

Supporting-Electrolyte-Free and Scalable Flow Process for the Electrochemical Synthesis of 3,3′,5,5′-Tetramethyl-2,2′-biphenol

“…Since pyridine is a liquid with a boiling point of 115 °C, it can easily be removed from the reaction mixture by distillation. It is noteworthy that the use of pyridine in HFIP does not lead to the pyridination reaction of electron-rich arene substrates to form the Zincke salts. − …”

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

“…[1] One powerful and emerging approach to detect and identify drug metabolites is the use of electrochemical techniques. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] An alternative approach is to computationally predict via docking how a drug might interact with a cytochrome. [16][17][18] However, approaches that interlink these two complementary techniques are not delineated at present.…”

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

“…An understanding of the major circulating metabolites that are generated from a parent bioactive molecule is of critical importance in drug discovery campaigns [1]. One powerful and emerging approach to detect and identify drug metabolites is the use of electrochemical techniques [2][3][4][5][6][7][8][9][10][11][12][13][14]. An alternative approach is to computationally predict via docking how a drug might interact with a cytochrome P 450 enzyme [15][16][17].…”