STRUCTURE AND MECHANISM OF DNA INTERSTRAND CROSSLINKING

建议在核酸化学领域进行研究。共价 将研究DNA链间交联剂的反应。 两个链间交联剂的化学结构 氮芥末和一种高度简化的还原类似物 活化的丝裂霉素C将在原子分辨率下通过 结构均一的链间交联DNA的水解性 含有这些交联物的碎片。由此产生的 将通过与真实的、合成的 预期结合物的样本。丝裂霉素的作用机制 DNA中优先交联5‘-CG序列的类似物将是 使用合理设计的合成类似物进行研究，链间 将在以下位置确定其交联序列首选项 核苷酸解析。双官能性烷基化试剂有望在 优先交联碱基序列5‘-GC的机械基础 将被合成和研究。DNA链间交联剂 能够识别和交联DNA的六个碱基对序列 将被设计和评估。

Research is proposed in the area of nucleic acid chemistry. Covalent reactions of DNA interstrand crosslinking agents will be investigated. The chemical structures of two interstrand crosslinks, those of a nitrogen mustard and of a highly simplified analog of reductively activated mitomycin C, will be determined at atomic resolution by hydrolysis of structurally homogeneous, interstrand crosslinked DNA fragments containing these crosslinks. The structures of the resulting conjugates will be identified by comparison to authentic, synthetic samples of the expected conjugates. The mechanism by which mitomycin analogs preferentially crosslink 5'-CG sequences in DNA will be investigated using rationally designed synthetic analogs, the interstrand crosslinking sequence preferences of which will be determined at nucleotide resolution. Bifunctional alkylating agents expected on mechanistic grounds to preferentially crosslink the base sequence 5'-GC will be synthesized and studied. DNA interstrand crosslinking agents capable of recognizing and crosslinking a six base pair sequence of DNA will be designed and evaluated.