An Improved Method for the Synthesis of 3‐Amino‐1H‐quinolin‐2‐one.

Juarez‐Gordiano, Cecilia; Hernández‐Campos, Alicia; Castillo, Rafael

doi:10.1002/chin.200301138

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“…Using an uncharacterized substrate (3-aminoquinoline), we demonstrate the utility of ecoAO to generate milligram quantities of AO metabolite from frozen cell paste reconstituted in buffer that can be used as starting material for the synthesis of more complex molecules. The biotranformation of 3-aminoquinoline, post-ecoAO 2-oxo-3-aminoquinoline analogue synthesis ( Scheme 3 ), and ecoAO metabolism of the 3-aminoquinoline analogues, illustrate two important points: (1) these metabolites could not be synthesized by the same method as was used for zoniporide (see Scheme 1 ), although a 4-step synthesis has been reported 37 and (2) even relatively sterically hindered compounds readily undergo oxidation adjacent to the nitrogen. From a broader perspective, the ecoAO system could also be employed in other settings where selective oxidation of azaheterocycles is desired in a synthesis.…”

Section: Discussionmentioning

confidence: 99%

ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism

et al. 2017

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Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO’s preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles. Here, we describe a practical bacterial biotransformation system, ecoAO, addressing both issues simultaneously. ecoAO is a cell paste of MoCo-producing Escherichia coli strain TP1017 expressing human AO. It exhibits specific activity toward known substrates, zoniporide, 4-trans-(N,N-dimethylamino)cinnamaldehyde, O6-benzylguanine, and zaleplon; it also has utility as a biocatalyst, yielding milligram quantities of synthetically challenging metabolite standards such as 2-oxo-zoniporide. Moreover, ecoAO enables routine determination of kcat and V/K, which are essential parameters for accurate in vivo clearance predictions. Furthermore, ecoAO has potential as a preclinical in vitro screening tool for AO activity, as demonstrated by its metabolism of 3-aminoquinoline, a previously uncharacterized substrate. ecoAO promises to provide easy access to metabolites with the potential to improve pharmacokinetic clearance predictions and guide drug development.

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Section: Discussionmentioning

confidence: 99%