FUNCTIONAL ANALOGS OF ENE-DIYNE TOXINS

烯二炔类毒素功能模型的设计与合成 这项提议的主要目的。长远目标是发展 基于抗生素活性新机制的选择性细胞毒药物。 Calicheamicins，espericicins和dynemicins是剧毒的物种 巧妙的激活机制，这在 确定了天然结构。随着这些机制现在很大程度上 在体外研究的支持下，有可能设计出具有 所有激活功能，但将随时提供数量， 可量身定做，避免外周毒性，并可有方便 用于与抗体等递送剂结合的系链。 Calicheamicin的模型是基于由 桥头烯醇双键的烯醇到酮互变，一个变化 类似于天然系列中桥头双键的加成。 然而，关键的触发步骤将是解除烯醇的阻塞，并且 手术可以设计成涉及几种不同的生物 机制，包括提议的天然二硫化物交换 产品。其结果将是一个简化的弹头模型或 苷元，可被触发产生高能双基，在 生理条件。一项合作努力将评估新的 化合物作为选择性DNA裂解剂，并安排附着 给药系统的更活跃的衍生品，包括单环素 抗体与天然产物的结合物目前正在研究中。 动力霉素的研究较少，并为 通过综合来建模。在这种情况下，关于 机制从简化的模型和模型本身可以作为新的 毒品候选人。显然，触发机制是不同的 涉及生物还原烷基化，并且功能模型可能具有 与Calicheamicins相比，活性特征非常不同。 与功能模型的综合相关的是一种有用的类型 应能促进烯-二炔系列合成的中间体 一般说来。前驱体的几何形状应该能形成关键的环 反应更有效，并保持中间体稳定，直到

The design and synthesis of functional models of the enediyne toxins is the primary aim of this proposal. The long range goal is the development of selective cytotoxic drugs based on novel mechanisms of antibiotic activity. The calicheamicins, esperimicins, and dynemicins are highly toxic species wit elegant mechanisms of activation which were not anticipated before the natural structures were determined. With the mechanisms now largely 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. The models for calicheamicin are based on a geometry change provoked by enol to keto tautomerization of a bridgehead enol double bond, a change similar to the addition to a bridgehead double bond in the natural series. However, the key triggering step will be de-blocking of the enol, and that operation can be designed to involve several different biological mechanisms, including disulfide exchange as proposed 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 collaborative effort will evaluate the new compounds as selective DNA cleavage agents and arrange attachment of the more active derivatives to delivery systems, including the monocionnal antibody conjugate now under study with the natural products. Dynemicin is less well studied, and offers similar opportunities for modeling by synthesis. In this case, much will be revealed about the mechanism from simplified models and the models themselves can serve as new drug candidates. The triggering mechanism is different, apparently involving bioreductive alkylation, and the functional models may have a very different profile of activity oompared to the calicheamicins. Connected with the synthesis of functional models is a useful type of intermediate which should facilitate synthesis in the ene-diyne series generally. The geometry of the precursor should make key ring-forming reactions more efficient, and keep the intermediates stabilized until