BACKGROUND Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling. RESULTS Here, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts. CONCLUSION The first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.

中文翻译：

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NQO1与化疗二聚萘醌之间的直接相互作用。

背景技术多聚萘醌是具有抗肿瘤，抗原生动物和抗病毒活性的氧化还原活性化合物。由于它们对细胞氧化状态的扰动具有多峰作用，因此这些化合物作为针对高度增殖性赘生性细胞的治疗剂具有巨大潜力。在我们以前的工作中，我们开发了一系列新颖的二聚萘醌，并显示它们对人急性髓细胞性白血病（AML），乳腺癌和前列腺癌细胞系具有选择性的细胞毒性。我们随后确定了氧化还原酶NAD（P）H脱氢酶醌1（NQO1）为二聚萘醌的主要靶标，并提出了诱导无效的氧化还原循环的作用机理。结果在这里，这是第一次 我们描述了溴羟基二聚萘醌E6a和NQO1之间的直接物理相互作用。此外，我们的研究揭示了E6a与NQO1的黄素腺嘌呤二核苷酸（FAD）辅因子的异四嗪环之间的广泛结合界面，以及与活性位点中蛋白质侧链的相互作用。我们还提供了生化证据，即二聚萘醌会影响NQO1的FAD辅助因子的氧化还原状态。E6a与其他化学疗法的结合方式的比较显示出相互作用的独特特征，可以在未来的药物优化工作中加以利用。结论报道了二聚萘醌-NQO1复合物的第一结构，