Quinoline-Based Compounds Can Inhibit Diverse Enzymes That Act on DNA

Authors

Jujun Zhou
Qin Chen
Ren Ren
Jie Yang
Bigang Liu
John R Horton
Caleb Chang
Chuxuan Li
Leora Maksoud
Yifei Yang
Dante Rotili
Abhinav K Jain
Xing Zhang
Robert M Blumenthal
Taiping Chen
Yang Gao
Sergio Valente
Antonello Mai
Xiaodong Cheng

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

Post-print

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, BER glycosylases, DNA adeinine methyltransferases, DNA cytosine methyltransferases, DNA hypomethylating agents, DNA intercalation, DNA/RNA polymerases, non-nucleoside compound, p53 response, pan inhibitors of DNA-acting enzymes, quinoline-based analogs

Published Open-Access

yes

Recommended Citation

Zhou, Jujun; Chen, Qin; Ren, Ren; et al., "Quinoline-Based Compounds Can Inhibit Diverse Enzymes That Act on DNA" (2024). Faculty, Staff and Student Publications. 4292.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4292