Reactivity and Dynamics of Enediyne Natural Products

描述(由申请人提供)：这项拟议研究的目标是使用先进的计算方法来彻底了解烯二炔系列天然产物切割DNA的机制。这些信息将指导实验者努力合成对肿瘤细胞更具选择性、对健康细胞毒性更小的烯二炔药物。目前，合成的努力是由一个普遍接受的假设指导的，即天然产物中的烯二炔环环化生成一种反应性的双自由基物种，从DNA骨架中提取氢。然而，还有其他的可能性。最近的实验证据表明，在生物条件下，烯二炔类化合物可以转化为高度细胞毒性的苯醌。6或者，环化和氢原子提取可以协同进行，而不会形成双自由基中间体。7如果这种机制正确，将迫使药物设计者从根本上改变他们的合成策略。我们将使用结合高水平电子结构理论和低水平半经验或分子力学方法的计算方法来准确地模拟天然产物烯二炔。我们对这个项目有几个明确的目标。我们的第一个工作假设是，烯二炔类分子在其弹头环化过程中通过一种协同机制从DNA中提取氢。我们的第二个工作假设是，连接到烯二炔部分的糖负责使天然产物与DNA接触。我们将通过获得天然产物环化和氢提取的可能途径的能量分布来检验第一个假设。然后，我们将确定分子的哪些部分是第一步中发现的较低反应路径所必需的。第二个假设将通过开发适合与AMBER8一起使用的endiynes天然产品的参数来验证。8.然后，我们将进行分子动力学模拟，显示烯二炔类糖对DNA识别过程的影响。

DESCRIPTION (provided by applicant): The goal of this proposed research is to use advanced computational methods to gain a thorough understanding of the mechanism of DNA cleavage by the enediyne family of natural products. This information will guide efforts by experimentalists to synthesize enediyne drugs that are more selective towards tumor cells, and less toxic towards healthy cells. Currently, synthetic efforts are directed by the commonly accepted assumption that the enediyne rings in the natural products cyclize to generate a reactive diradical species that abstracts hydrogen from the DNA backbone. 1-5 However, there are other possibilities. Recent experimental evidence has shown that enediynes can be converted to highly cytotoxic quinones under biological conditions.6 Alternatively, the cyclization and hydrogen atom abstraction could be concerted, without the formation of a diradical intermediate.7 If correct, such mechanisms would force drug designers to radically alter their synthetic strategies. We will use computational methods that integrate high-level electronic structure theory and low-level semiempirical or molecular mechanics methods to accurately model the natural product enediynes. We have several explicit goals for this project. Our first working hypothesis is that enediynes extract hydrogen from DNA through a concerted mechanism during the cyclization of their warheads. Our second working hypothesis is that the sugars attached to the enediyne moiety are responsible for bringing the natural products into contact with DNA. We will test the first hypothesis by obtaining energetic profiles of the possible pathways for cyclization and hydrogen abstraction of the natural products. Then, we will determine which portions of the molecule are essential for the lower reaction pathways found in step one. The second hypothesis will be tested by developing parameters for the enediynes natural products suitable for use with AMBER8. 8.Then, we will run Molecular Dynamics simulations that will show the effect of the enediynes sugars on the DNA recognition process.