Quinoline-based compounds can inhibit diverse enzymes that act on DNA.

Autor:	Zhou J; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Chen Q; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Ren R; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Yang J; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Liu B; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Horton JR; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Chang C; Department of Biosciences, Rice University, Houston, TX 77005, USA., Li C; Department of Biosciences, Rice University, Houston, TX 77005, USA., Maksoud L; Department of Biosciences, Rice University, Houston, TX 77005, USA., Yang Y; Department of Biosciences, Rice University, Houston, TX 77005, USA., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy., Jain AK; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Zhang X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Blumenthal RM; Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Chen T; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Gao Y; Department of Biosciences, Rice University, Houston, TX 77005, USA., Valente S; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy., Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy., Cheng X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: xcheng5@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1016/j.chembiol.2024.09.007
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interest. (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu