Biomimetic Cyclization of Substituted N-Aryl-Amino Pyrrolopyri(mi)dines using Micro-Preparative Electrochemistry/Mass Spectrometry

摘要

Enzymatic drug metabolism can be divided in two groups, Phase I reactions (functionalization) and Phase II reactions (conjugation). Phase I metabolites are typically formed by oxidation, reduction and hydrolysis. Oxidative metabolism is catalyzed by specific enzymes (e.g. Cytochrome P450) in the presence of different cellular e-/H+ acceptors and donors (O_2 and cofactors like NADPH). By analogy, electrochemistry is a synthetic route which can generate identical oxidized or reduced products from e-/H+ transfer or radical reactions (discharge of H_2O). Structure elucidation of metabolites is an important task in drug discovery. Besides well-established in vitro assays and in vivo animal models, several biomimetic methods are described in literature. Among these methods, electrochemistry can be used as a compl ementary method for simulation of the oxidative metabolism of xenobiotics. The advantage of the method is the simple online coupling to mass spectrometry for monitoring of the desired metabolic reaction and its application for the micro-scaled synthesis of metabolites. The isolated products can be obtained on a μg-scale at purities >90% which are finally analyzed by cryo-probe NMR for structure elucidation.