Quinoline-based compounds can inhibit diverse enzymes that act on DNA
Abstract DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine (9) or methylpiperazine (11) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) andClostridioides difficileCamA (which generates N6-methyladenine). Structurally, compounds9and11specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound11elicits DNA damage response via p53 activation.Abstract Figure <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="587980v1_ufig1" position="float" orientation="portrait" /></jats:fig>Highlights <jats:list list-type="bullet">Six of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferasesClostridioides difficileCamA andCaulobacter crescentusCcrM.Compounds9and11were found to intercalate into a DNA substrate bound by CamA.These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases.Compound11provokes DNA damage response via p53 activation in cancer cells..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 06. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhou, Jujun [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.04.03.587980 |
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| 520 | |a Abstract DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine (9) or methylpiperazine (11) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) andClostridioides difficileCamA (which generates N6-methyladenine). Structurally, compounds9and11specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound11elicits DNA damage response via p53 activation.Abstract Figure <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="587980v1_ufig1" position="float" orientation="portrait" /></jats:fig>Highlights <jats:list list-type="bullet">Six of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferasesClostridioides difficileCamA andCaulobacter crescentusCcrM.Compounds9and11were found to intercalate into a DNA substrate bound by CamA.These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases.Compound11provokes DNA damage response via p53 activation in cancer cells. | ||
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