The Leaving Group Strongly Affects H2O2‑Induced DNA Cross-Linking by Arylboronates

We evaluated the effects of the benzylic leaving group and core structure of arylboronates on H2O2-induced formation of bisquinone methides for DNA interstrand cross-linking. The mechanism of DNA cross-linking induced by these arylboronates involves generation of phenol intermediates followed by departure of benzylic leaving groups leading to QMs which directly cross-link DNA via alkylation. The QM formation is the rate-determining step for DNA cross-linking. A better leaving group (Br) and stepwise bisquinone methide formation increased interstrand cross-linking efficiency. These findings provide essential guidelines for designing novel anticancer prodrugs.我们评估了芳基硼酸酯（arylboronates）的苄基离去基团（benzylic leaving group）与核心结构，对过氧化氢（H₂O₂）诱导的用于DNA链间交联的双醌甲基化物（bisquinone methides）生成的影响。此类芳基硼酸酯所诱导的DNA交联机制，涉及酚中间体的生成，随后苄基离去基团脱离，生成醌甲基化物（QM，quinone methides），该中间体可通过烷基化反应直接与DNA发生链间交联。醌甲基化物的生成是DNA交联过程的决速步。使用更优异的离去基团（溴，Br）以及采用分步式双醌甲基化物生成路径，可有效提升DNA链间交联效率。本研究发现为新型抗癌前药（anticancer prodrugs）的设计提供了关键指导准则。