FUNCTIONAL ANALOGS OF THE ENE-DIYNE TOXINS

烯-二炔毒素功能模型的设计与合成 这项提议的主要目的是。这将导致...的发展 基于抗生素新作用机制的选择性细胞毒药物 活动。Calicheamicins、espericins和dynemycins的含量很高 具有优雅的激活机制的有毒物种 在自然结构确定之前就已经预料到了。与 机制现在得到了体外研究的很好支持，有可能 设计具有所有激活功能的模拟，但将是 数量充足，可量身定做，避免外设 毒性，并可以有方便的系链与输送连接 抗体等试剂。 已经演示了一种Calicheamicin模型，并将进行详细说明 在本授权期内。关键触发步骤是解除阻塞 该操作可以被设计为涉及几个不同 生物机制，包括为二硫化物交换建立的 天然产品。其结果将是“弹头”的简化模型。 或苷元，它可以被触发产生高能双基 生理条件。第二个通用触发机制将是 基于相同的Calicheamicin骨架，但构象不同 调整，轮椅环己烷。一套相似的生理上的 兼容的过程将被设计成构象触发器。一个 与美国医学研究部的合作努力 氰胺将评估新化合物作为选择性DNA裂解剂 并安排将更活跃的衍生物连接到递送系统上， 包括目前在氰胺研究所研究的单抗结合物 天然产物本身。 一个重要的方面是对各种DNA递送剂的评估， 对上一次赠款期间使用netropsin的结果进行跟踪。 烯二炔在DNA切割中的效力对 DNA上的定位和递送剂的适当设计是一种 关键组件。

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.