FUNCTIONAL ANALOGS OF ENE-DIYNE TOXINS

烯-二因毒素的功能类似物

• 批准号: 3199360
• 负责人: MARTIN F SEMMELHACK
• 金额: $ 11.65万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3199360
• 关键词: DNA; alkylation; alkynes; antineoplastic antibiotics; chemical cleavage; chemical models; chemical stability; chemical structure function; chemotherapy; chromatography; cytotoxicity; disulfide bond; drug adverse effect; drug delivery systems; drug design /synthesis /production; enol; free radicals; glutamyltransferase; immunoconjugates; ketones; peptide chemical synthesis; tautomer; toxin

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

烯二炔类毒素功能模型的设计与合成是研究的重点 这一提案的主要目的。 长期目标是发展 基于抗生素活性新机制的选择性细胞毒性药物。 卡奇霉素、埃斯帕里霉素和动力霉素是高毒性物质 巧妙的激活机制，这是以前没有预料到的， 天然结构已确定。 现在的机制主要是 在体外研究的支持下，有可能设计出类似物， 所有的激活特征，但将容易大量获得， 可以定制以避免外周毒性，并且可以具有方便的 用于与递送剂如抗体缀合的系链。 加利车霉素的模型是基于几何形状的变化， 烯醇到酮的互变异构化的一个桥头烯醇双键， 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烯醇的去封闭， 操作可以被设计为涉及几种不同的生物学 机制，包括二硫键交换提出的天然 产品. 其结果将是“弹头”的简化模型， 糖苷配基，其可以在 生理条件。 一项合作努力将评估新的 化合物作为选择性DNA切割剂，并安排连接的 更多的活性衍生物，包括单克隆抗体 抗体结合物目前正在研究与天然产物。 Dynemicin的研究较少，并提供了类似的机会， 综合建模 在这种情况下，将揭示很多关于 从简化的模型和模型本身可以作为新的机制 候选药物 很明显，触发机制不同 涉及生物还原性烷基化，并且功能模型可能具有 与卡奇霉素的活性非常不同。 与功能模型的合成有关的是一种有用的 促进烯-二炔系列合成的中间体 一般来说。 前体的几何形状应使键环成形 反应更有效，并保持中间体稳定，