FUNCTIONAL ANALOGS OF ENE-DIYNE TOXINS

烯-二因毒素的功能类似物

• 批准号: 3199357
• 负责人: MARTIN F SEMMELHACK
• 金额: $ 11.39万
• 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/3199357
• 关键词: DNA; alkylation; alkynes; antineoplastic antibiotics; chemical cleavage; chemical models; chemical stability; chemical structure function; chemotherapy; chromatography; cytotoxicity; 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

Enediyne毒素功能模型的设计和合成是 该提议的主要目的。 远距离目标是发展 基于抗生素活性的新机制的选择性细胞毒性药物。 钙蛋白，厄克糖蛋白和天生蛋白是剧毒的物种 机智优雅的激活机制，在 确定自然结构。 现在的机制很大程度上 在体外研究的支持下，可以设计具有 所有激活功能都将很容易获得数量， 可以量身定制以避免外围毒性，并且可以方便 与抗体等递送剂共轭的tethers。 Calicheamicin的模型是基于由几何变化引起的 烯醇到桥头旋转enol双键的酮互变异分解，变化 与自然系列中的桥头双键相似。 但是，关键触发步骤将是enol的堵塞，并且 操作可以设计为涉及几种不同的生物学 机制，包括为天然提出的二硫键交换 产品。 结果将是“弹头”或 可以触发以在下面产生高能量的aglycone 生理条件。 协作努力将评估新的 化合物作为选择性DNA裂解剂，并安排附着的附件 对输送系统的更活跃的衍生物，包括单元成分 抗体结合物现在正在研究天然产物。 Dynemicin的研究较少，并提供了类似的机会 通过合成建模。 在这种情况下，关于 简化模型的机制，模型本身可以作为新的机制 候选毒品。 触发机制是不同的，显然是 涉及生物学烷基化，功能模型可能具有 与卡利希蛋白相比的活动概况截然不同。 与功能模型的合成相关的是有用的类型 中间体应促进ene-diyne系列中的合成 一般来说。 前体的几何形状应使键环形成 反应更有效，并保持中间体稳定直到