Metallodrugs provide important first-line treatment against various forms of human cancer. To overcome chemotherapeutic resistance and widen treatment possibilities, new agents with improved or alternative modes of action are highly sought after. Here, we present a click chemistry strategy for developing DNA damaging metallodrugs. The approach involves the development of a series of polyamine ligands where three primary, secondary or tertiary alkyne-amines were selected and ‘clicked’ using the copper-catalysed azide-alkyne cycloaddition reaction to a 1,3,5-azide mesitylene core to produce a family of compounds we call the ‘Tri-Click’ (TC) series. From the isolated library, one dominant ligand (TC1) emerged as a high-affinity copper(II) binding agent with potent DNA recognition and damaging properties. Using a range of in vitro biophysical and molecular techniques—including free radical scavengers, spin trapping antioxidants and base excision repair (BER) enzymes—the oxidative DNA damaging mechanism of copper-bound TC1 was elucidated. This activity was then compared to intracellular results obtained from peripheral blood mononuclear cells exposed to Cu(II)–TC1 where use of BER enzymes and fluorescently modified dNTPs enabled the characterisation and quantification of genomic DNA lesions produced by the complex. The approach can serve as a new avenue for the design of DNA damaging agents with unique activity profiles.

中文翻译：

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Click and Cut：开发氧化 DNA 损伤剂的点击化学方法


金属药物为各种形式的人类癌症提供重要的一线治疗。为了克服化疗耐药性并扩大治疗可能性，具有改进或替代作用模式的新药物受到高度追捧。在这里，我们提出了一种用于开发 DNA 损伤金属药物的点击化学策略。该方法涉及开发一系列多胺配体，其中选择三种伯、仲或叔炔胺，并使用铜催化的叠氮-炔环加成反应“点击”至1,3,5-叠氮均三甲苯核心，产生我们称之为“Tri-Click”(TC) 系列的一系列化合物。从分离的文库中，出现了一种优势配体 (TC1)，它是一种高亲和力的铜 (II) 结合剂，具有有效的 DNA 识别和破坏特性。使用一系列体外生物物理和分子技术（包括自由基清除剂、自旋捕获抗氧化剂和碱基切除修复 (BER) 酶），阐明了铜结合 TC1 的氧化 DNA 损伤机制。然后将该活性与暴露于 Cu(II)-TC1 的外周血单核细胞获得的细胞内结果进行比较，其中使用 BER 酶和荧光修饰的 dNTP 能够对复合物产生的基因组 DNA 损伤进行表征和定量。该方法可以作为设计具有独特活性特征的 DNA 损伤剂的新途径。