FUNCTIONAL ANALOGS OF THE ENE-DIYNE TOXINS

本论文的目的是设计和合成烯二炔类毒素的功能模型， 这是该提案的主要目的。 这将导致发展 基于抗生素新机制的选择性细胞毒性药物 活动 加利车霉素、埃斯帕里霉素和动力霉素是高度可接受的。 具有优雅的激活机制的有毒物质， 在确定自然结构之前， 与 目前，体外研究充分支持了这一机制， 具有所有激活特征的设计类似物， 易于获得的数量，可以量身定制，以避免周边 毒性，并且可以具有方便的栓系物用于与递送结合 试剂如抗体。 加利车霉素的一个模型已经被证明，并将详细说明 在目前的补助期内。 关键的触发步骤是对 烯醇和操作可以被设计为涉及几种不同 生物学机制，包括二硫键交换， 天然产品。 其结果将是一个简化模型的“弹头” 或糖苷配基，其可以在 生理条件。 第二种通用触发机制将是 基于相同的加利车霉素框架，但不同的构象 调整，船椅环己烷。 一套类似的生理学 将相容过程设计到构象触发剂中。 一 与美国医学研究部合作， 氰胺将评估新化合物作为选择性DNA切割剂 并将活性更高的衍生物连接到递送系统上， 包括Cyanamid正在研究的单克隆抗体结合物 天然产品本身。 一个重要的方面是评估各种DNA递送剂， 跟踪上一个资助期内使用netropsin的结果。 烯二炔在DNA切割中的效力对以下因素非常敏感： 在DNA上的定位和递送剂的适当设计是 关键部件。

The design and synthesis of functional models of the ene-diyne toxins is the primary aim of this proposal. This will lead to the development of selective cytotoxic drugs based on novel mechanisms of antibiotic activity. The calicheamicins, esperimicins, and dynemycins are highly toxic species with elegant mechanisms of activation which were not anticipated before the natural structures were determined. With the mechanisms now well supported by in vitro studies, it is possible to design analogs which have all of the activation features, but will be readily available in quantity, can be tailored to avoid peripheral toxicity, and can have convenient tethers for conjugation with delivery agents such as antibodies. One model for calicheamicin has been demonstrated and will be elaborated in the current grant period. The key triggering step is de-blocking of the enol, and that operation can be designed to involve several different biological mechanisms, including disulfide exchange as established for the natural products. The result will be a simplified model for the "warhead" or aglycone which can be triggered to produce high energy diradicals under physiological conditions. A second general triggering mechanism will be based on the same calicheamicin framework, but a different conformation adjustment, boat-chair cyclohexane. A similar set of physiologically compatible processes will be designed into the conformational trigger. A collaborative effort with the Medical Research Division of American Cyanamid will evaluate the new compounds as selective DNA cleavage agents and arrange attachment of the more active derivatives to delivery systems, including the monoclonal antibody conjugate now under study at Cyanamid with the natural product itself. An important aspect is the evaluation of various DNA delivery agents, following up on the results with netropsin in the previous grant period. The potency of the enediyne in DNA cleavage is very sensitive to positioning on the DNA and proper design of the delivery agents is a critical component.