DNA alkylation and crosslinking remains a common and effective strategy for anticancer chemotherapy despite its infamous lack of specificity. Coupling a reactive group to a sequence-directing component has the potential to enhance target selectivity but may suffer from premature degradation or the need for an external signal for activation. Alternatively, quinone methide conjugates may be employed if they form covalent but reversible adducts with their sequence directing component. The resulting self-adducts transfer their quinone methide to a chosen target without an external signal and avoid off-target reactions by alternative intramolecular self-trapping. Efficient transfer is shown to depend on the nature of the quinone methide and the sequence-directing ligand in applications involving alkylation of duplex DNA through a triplex recognition motif. Success required an electron-rich derivative that enhanced the stability of the transient quinone methide intermediate and a polypyrimidine strand of DNA to associate with its cognate polypurine/polypyrimidine target. Related quinone methide conjugates with peptide nucleic acids were capable of quinone methide transfer from their initial precursor but not from their corresponding self-adduct. The active peptide nucleic acid derivatives were highly selective for their complementary target.

中文翻译：

---

靶向具有可逆反应性醌甲基化物的双链DNA。

尽管众所周知，DNA烷基化和交联仍然是抗癌化学治疗的一种常见且有效的策略。将反应性基团偶联至序列指导组分具有增强靶标选择性的潜力，但可能遭受过早降解或需要用于激活的外部信号的困扰。或者，如果醌甲基化物缀合物与它们的序列指导组分形成共价但可逆的加合物，则可以使用。所得的自加合物将其醌甲基化物转移到选定的靶标，而没有外部信号，并通过可选的分子内自陷避免了脱靶反应。在涉及通过三链体识别基序使双链体DNA烷基化的应用中，有效转移显示出取决于醌甲基化物和序列指导配体的性质。成功需要富电子的衍生物来增强瞬态醌甲基化物中间体和DNA的聚嘧啶链的稳定性，以与其同源的聚嘌呤/聚嘧啶靶标缔合。与肽核酸相关的醌甲基化物缀合物能够从其初始前体转移醌甲基化物，但不能从其相应的自加合物转移。活性肽核酸衍生物对其互补靶具有高度选择性。成功需要富电子的衍生物来增强瞬态醌甲基化物中间体和DNA的聚嘧啶链的稳定性，以与其同源的聚嘌呤/聚嘧啶靶标缔合。与肽核酸相关的醌甲基化物缀合物能够从其初始前体转移醌甲基化物，但不能从其相应的自加合物转移。活性肽核酸衍生物对其互补靶具有高度选择性。成功需要富电子的衍生物，以增强瞬态醌甲基化物中间体和DNA的聚嘧啶链的稳定性，以与其关联的聚嘌呤/聚嘧啶靶标结合。与肽核酸相关的醌甲基化物缀合物能够从其初始前体转移醌甲基化物，但不能从其相应的自加合物转移。活性肽核酸衍生物对其互补靶具有高度选择性。