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

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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 ( IF 3.5 ) Pub Date : 2020-12-17 , DOI: 10.1021/acschembio.0c00877
Melis Kant ₁ , Yu-Ki Tahara ₂ , Pawel Jaruga ₁ , Erdem Coskun _{1,

3} , R Stephen Lloyd ₄ , Eric T Kool ₂ , Miral Dizdaroglu ₁

Affiliation

DNA glycosylases involved in the first step of the DNA base excision repair pathway 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.

中文翻译：

四氢喹啉磺酰胺衍生物对氧化诱导的 DNA 碱基损伤的几种产物的人 8-氧鸟嘌呤 DNA 糖基化酶 (OGG1) 活性的抑制作用

参与 DNA 碱基切除修复途径第一步的 DNA 糖基化酶是癌症治疗的有希望的靶点。有证据表明，降低它们的活性可能会增强恶性肿瘤中的细胞杀伤力。最近，据报道，两种名为 SU0268 和 SU0383 的四氢喹啉化合物可抑制 OGG1 切除 8-羟基鸟嘌呤。这种 DNA 修复蛋白是一种主要的细胞酶，负责从 DNA 中切除许多氧化诱导的损伤。在这项工作中，我们使用带有同位素稀释的气相色谱-串联质谱法不仅测量了 8-羟基鸟嘌呤的切除，还测量了 OGG1 的其他主要底物，即 2,6-二氨基-4-羟基-5 的切除。 -甲酰胺嘧啶，使用具有多个嘌呤和嘧啶衍生病变的基因组 DNA。切除次要基质4，还测量了 6-二氨基-5-甲酰胺嘧啶。SU0268 和 SU0383 都有效抑制了这三种病变的 OGG1 活性，前者比后者更有效。还证明了抑制对 SU0268 和 SU0383 浓度从 0.05 μmol/L 到 10 μmol/L 的依赖性。本工作中使用的方法可用于研究 SU0268 和 SU0383 以及其他小分子抑制剂对 OGG1 的抑制作用，以进行进一步的研究，包括疾病的细胞和动物模型。

更新日期：2021-01-15

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