Language

English

Publication Date

12-19-2024

Journal

Cell Chemical Biology

DOI

10.1016/j.chembiol.2024.09.007

PMID

39437789

PMCID

PMC11663113

PubMedCentral® Posted Date

12-19-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a 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. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound 11 elicits DNA damage response via p53 activation in cancer cells.

Keywords

Humans, Quinolines, DNA (Cytosine-5-)-Methyltransferase 1, DNA, Enzyme Inhibitors, Clostridioides difficile, Structure-Activity Relationship, DNA Methylation, Molecular Structure, Bacterial Proteins, DNA hypomethylating agents, DNA intercalation, quinoline-based analogs, non-nucleoside compound, pan inhibitors of DNA-acting enzymes

Published Open-Access

yes

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