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.

中文翻译：

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基于喹啉的化合物可以抑制作用于 DNA 的各种酶


DNA 甲基化，如哺乳动物中的胞嘧啶-C5 甲基化和细菌中的腺嘌呤-N6 甲基化，是一个关键的表观遗传过程。开发非核苷抑制剂以引起 DNA 低甲基化对于治疗各种疾病至关重要，而没有与现有基于胞苷的低甲基化药物相关的毒性。本研究表征了 15 种基于喹啉的类似物，特别是添加了甲胺 （9） 或甲基哌嗪 （11） 等化合物，它们对人 DNMT1 和艰难梭菌 CamA 表现出相似的低微摩尔抑制效力。这些化合物（9 和 11）通过小沟嵌入到 CamA 结合的 DNA 中，导致构象变化，使催化结构域远离 DNA。这项研究增加了 DNA 甲基转移酶通过 DNA 嵌入被非核苷酸化合物抑制的有限例子。此外，一些基于喹啉的类似物会抑制其他 DNA 相互作用酶，例如聚合酶和碱基切除修复糖基化酶。最后，化合物 11 通过癌细胞中的 p53 激活引发 DNA 损伤反应。