Trioxacarcin A Interactions with G-Quadruplex DNA Reveal Its Potential New Targets as an Anticancer Agent,Journal of Medicinal Chemistry

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Trioxacarcin A Interactions with G-Quadruplex DNA Reveal Its Potential New Targets as an Anticancer Agent
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-08 , DOI: 10.1021/acs.jmedchem.3c00178
Shaowen Yin _{1,

2} , Wenxian Lan ₃ , Xianfeng Hou ₁ , Zhijun Liu ₄ , Hongjuan Xue ₄ , Chunxi Wang ₁ , Gong-Li Tang ₁ , Chunyang Cao _{1,

2,

5}

Affiliation

Trioxacarcin (TXN) A was reported to be an anticancer agent through alkylation of dsDNA. G-quadruplex DNA (G4-DNA) is frequently formed in the promoter regions of oncogenes and the ends of telomerase genes, considered as promising drug targets for anticancer therapy. There are no reports about TXN A interactions with G4-DNA. Here, we tested TXN A’s interactions with several G4-DNA oligos with parallel, antiparallel, or hybrid folding, respectively. We demonstrated that TXN A preferred to alkylate one flexible guanine in the loops of parallel G4-DNA. The position of the alkylated guanine is in favor of interactions of G4-DNA with TXN A. The structure of TXN A covalently bound RET G4-DNA indicated that TXN A alkylation on RET G4-DNA stabilizes the G4-DNA conformation. These studies opened a new window of how TXN A interacted with G4-DNA, which might hint a new mode of its function as an anticancer agent.

中文翻译：

Trioxacarcin A 与 G-四链体 DNA 的相互作用揭示了其作为抗癌药物的潜在新靶点

据报道，Trioxacarcin (TXN) A 通过 dsDNA 烷基化而成为一种抗癌剂。G-四链体 DNA (G4-DNA) 经常形成于癌基因的启动子区域和端粒酶基因的末端，被认为是有前景的抗癌药物靶点。目前还没有关于 TXN A 与 G4-DNA 相互作用的报道。在这里，我们分别通过平行、反平行或混合折叠测试了 TXNA A 与几种 G4-DNA 寡核苷酸的相互作用。我们证明 TXN A 优先将平行 G4-DNA 环中的一个柔性鸟嘌呤烷基化。烷基化鸟嘌呤的位置有利于G4-DNA与TXN A相互作用。TXN A共价结合RET G4-DNA的结构表明RET G4-DNA上的TXN A烷基化稳定了G4-DNA构象。这些研究打开了 TXN A 如何与 G4-DNA 相互作用的新窗口，

更新日期：2023-05-08

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