Targeting duplex DNA with the reversible reactivity of quinone methides.
Targeting duplex DNA with the reversible reactivity of quinone methides.
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DOI：
10.1038/sigtrans.2016.9
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发表时间：
2016
影响因子：
39.3
通讯作者：
Rokita SE
中科院分区：
文献类型：
--
作者：
Huang C;Liu Y;Rokita SE
DNA烷基化和交联仍然是抗癌化疗的常用和有效的策略，尽管其臭名昭著的缺乏特异性。将反应性基团偶联至序列导向组分具有增强靶选择性的潜力，但可能遭受过早降解或需要外部信号来激活。或者，如果醌甲基化物缀合物与其序列导向组分形成共价但可逆的加合物，则可以使用醌甲基化物缀合物。所得到的自加合物将其醌甲基化物转移到选定的靶点，而无需外部信号，并通过替代的分子内自捕获避免脱靶反应。有效的转移取决于醌甲基化物和序列导向配体的性质，在涉及通过三链体识别基序的双链体DNA的烷基化的应用中。成功需要一个富电子的衍生物，提高稳定性的瞬态醌甲基化物中间体和DNA的聚嘧啶链，以与其同源聚嘌呤/聚嘧啶目标。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醌甲基化物。活性肽核酸衍生物对它们的互补靶标具有高度选择性。
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.