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Electrochemical and in silico approaches for liver metabolic oxidation of antitumor-active triazoloacridinone C-1305

摘要5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) is a promising antitumor com-pound developed in our laboratory. A better understanding of its metabolic transformations is still needed to explain the multidirectional mechanism of pharmacological action of triazoloacridinone de-rivatives at all. Thus, the aim of the current work was to predict oxidative pathways of C-1305 that would reflect its phase Ⅰ metabolism. The multi-tool analysis of C-1305 metabolism included electrochemical conversion and in silico sites of metabolism predictions in relation to liver microsomal model. In the framework of the first approach, an electrochemical cell was coupled on-line to an electrospray ioni-zation mass spectrometer. The effluent of the electrochemical cell was also injected onto a liquid chromatography column for the separation of different products formed prior to mass spectrometry analysis. In silico studies were performed using MetaSite software. Standard microsomal incubation was employed as a reference procedure. We found that C-1305 underwent electrochemical oxidation pri-marily on the dialkylaminoalkylamino moiety. An unknown N-dealkylated and hydroxylated C-1305 products have been identified. The electrochemical system was also able to simulate oxygenation re-actions. Similar pattern of C-1305 metabolism has been predicted using in silico approach. Both proposed strategies showed high agreement in relation to the generated metabolic products of C-1305. Thus, we conclude that they can be considered as simple alternatives to enzymatic assays, affording time and cost efficiency.

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作者 Agnieszka Pot(e)ga [1] Dorota (Z)elaszczyk [2] Zofia Mazerska [1] 学术成果认领
作者单位 Department of Pharmaceutical Technology and Biochemistry,Faculty of Chemistry,Gdańsk University of Technology,Gabriela Narutowicza St. 11/12,Gdańsk,80-233,Poland [1] Department of Organic Chemistry,Faculty of Pharmacy,Jagiellonian University,Medyczna St. 9,Kraków,30-688,Poland [2]
栏目名称 Original Articles
发布时间 2020-09-17
基金项目
This work was supported by the National Science Center
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药物分析学报(英文)

药物分析学报(英文)

2020年10卷4期

376-384页

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