TARGET PROMOTED ALKYLATION OF NUCLEIC ACIDS

对DNA烷基化的研究兴趣继续保持在 关于核酸结构、毒理学和 药理学。烷化剂在化疗中的重要性不能 被低估了，尽管与此相关的严重并发症 治疗。DNA的选择性修饰通常归因于 改性剂的本征化学和结合性能 DNA通常充当被动的受体和反应的目标。这个 DNA作为催化剂并控制自身修饰的潜力 尽管取得了实质性的进展，但受到的关注有限 核糖核酸催化的相关领域。这项提案旨在揭示一个 新的，也许是通用的试剂激活机制，应该 扩大我们对潜在的诱变、化疗和 诊断反应物。 以前的研究表明，双链DNA可以激活硅基 用于烷基化和交联化的苯酚衍生物。这些衍生品 最初是为依赖氟化物的反应而建造的，但 发现在与靶核苷酸结合后发生自发反应 序列。这一过程的机制还有待发现。这个 拟议的调查将从本地化复式建筑区域开始 负责激活过程的DNA。这一机制将 然后部分由其官能团和构象定义 要求。这些因素将通过检查效果来确定。 结合到激活区的核苷酸类似物。 最后，硅基化学将扩展到新试剂。 设计和应用以增强其在体外和体内的应用前景 活着。因此，靶向修饰的效率和特异性 将在DNA、RNA和蛋白质复合体中进行检测，作为一种帮助 定义生物结构和反应性。我们领先的效率 化合物还将与各种细胞系进行测试并进行比较 到临床上使用的烷化剂。

Research interest in DNA alkylation continues to be sustained by numerous issues concerning nucleic acid structure, toxicology, and pharmacology. The importance of alkylating agents in chemotherapy cannot be underestimated despite the serious complications associated with such treatment. Selective modification of DNA is generally ascribed to the intrinsic chemistry and binding properties of the modifying agent since DNA typically acts as a passive receptor and target of reaction. The potential for DNA to act as a catalyst and control its own modification has received limited attention despite substantial advances in the related field of RNA catalysis. This proposal is designed to reveal a new and perhaps general mechanism of reagent activation that should broaden our understanding of potential mutagenic, chemotherapeutic and diagnostic reactants. Previous studies have demonstrated that duplex DNA can activate silyl phenol derivatives for alkylation and cross-linking. These derivatives had originally been constructed for fluoride-dependent reaction but were found to react spontaneously after binding to target nucleotide sequences. The mechanism of this process remains to be discovered. The proposed investigations will begin by localizing the region of duplex DNA that is responsible for the activation process. The mechanism will then be defined in part by its functional group and conformational requirements. These in turn will be identified by examining the effect of nucleotide analogues incorporated into the region of activation. Finally, the silyl-based chemistry will be extended to new reagent design and application to enhance its future utility in vitro and in vivo. Accordingly, the efficiency and specificity of target modification will be examined in DNA, RNA and protein complexes as a method to help define biological structure and reactivity. The efficiency of our lead compounds will also be tested with a variety of cell lines and compared to alkylating agents that are used clinically.