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.
展开▼
机译：据报道，Trioxacarcin （TXN） A 是一种通过 dsDNA 烷基化而产生的抗癌剂。G-四链体DNA（G4-DNA）通常形成于癌基因的启动子区域和端粒酶基因的末端，被认为是抗癌治疗的有前途的药物靶点。目前尚无关于TXN A与G4-DNA相互作用的报道。在这里，我们分别测试了TXN A与几种G4-DNA寡核苷酸的相互作用，这些寡核苷酸分别具有平行、反平行或杂交折叠。我们证明 TXN A 倾向于在平行 G4-DNA 的环中烷基化一个柔性鸟嘌呤。烷基化鸟嘌呤的位置有利于 G4-DNA 与 TXN A 的相互作用。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。这些研究为TXN A如何与G4-DNA相互作用打开了一扇新窗口，这可能暗示了其作为抗癌剂的新功能模式。
展开▼
