Inhibition by Tetrahydroquinoline Sulfonamide Derivatives of the Activity of Human 8-Oxoguanine DNA Glycosylase (OGG1) for Several Products of Oxidatively-induced DNA Base Lesions

Published

December 17, 2021

Author(s)

Miral M. Dizdar, Melis Kant, Pawel Jaruga, Erdem Coskun, Yu-Ki Tahara, R. S. Lloyd, Eric T. Kool

Abstract

DNA glycosylases involved in the first step of the base excision repair pathway of DNA repair are promising targets in cancer therapy. There is evidence that reduction of their activities may enhance cell killing in malignant tumors. Recently, two tetrahydroquinoline compounds named SU0268 and SU0383 were reported to inhibit OGG1 for the excision of 8-hydroxyguanine. This DNA repair protein is one of the major cellular enzymes responsible for excision of a number of oxidatively-induced lesions from DNA. In this work, we used gas chromatography-tandem mass spectrometry with isotope-dilution to measure the excision of not only 8-hydroxyguanine, but also that of the other major substrate of OGG1, i.e., 2,6-diamino-4-hydroxy-5-formamidopyrimidine, using genomic DNA with multiple purine- and pyrimidine-derived lesions. The excision of a minor substrate 4,6-diamino-5-formamidopyrimidine was also measured. Both SU0268 and SU0383 efficiently inhibited OGG1 activity for these three lesions, with the former being more potent than the latter. Dependence of inhibition on concentrations of SU0268 and SU0383 from 0.05 μmol/L to 10 μmol/L was also demonstrated. The approach used in this work may be applied to the investigation of OGG1 inhibition by SU0268 and SU0383, and other small molecule inhibitors in further studies including cellular and animal models of disease.

Citation

ACS Chemical Biology

Pub Type

Journals

Download Paper

https://doi.org/10.1021/acschembio.0c00877

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Keywords

OGG1, gas chromatography-tandem mass spectrometry, cancer therapy, inhibitors of DNA repair

Citation

Dizdar, M. , Kant, M. , Jaruga, P. , Coskun, E. , Tahara, Y. , Lloyd, R. and Kool, E. (2021), Inhibition by Tetrahydroquinoline Sulfonamide Derivatives of the Activity of Human 8-Oxoguanine DNA Glycosylase (OGG1) for Several Products of Oxidatively-induced DNA Base Lesions, ACS Chemical Biology, [online], https://doi.org/10.1021/acschembio.0c00877, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=930987 (Accessed December 4, 2024)