FUNCTIONAL ANALOGS OF THE ENEDIYNE TOXINS

烯乙炔毒素的功能类似物

基本信息

批准号：
6375904
负责人：
MARTIN F SEMMELHACK
金额：
$ 19.62万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 2002-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6375904
关键词：
DNA DNA damage adduct analog antimetabolites antineoplastic antibiotics chemical cleavage chemical conjugate chemical structure function chemical synthesis computer simulation cytotoxicity drug design /synthesis /production enol free radicals prodrugs thermodynamics

项目摘要

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.

Ene-Diyne毒素功能模型的设计和合成是该提议的主要目的。这将导致发展基于抗生素的新机制的选择性细胞毒性药物活动。 Calicheamicins，Esperimicins和dynemycins高度高有毒物种具有优雅的激活机制在确定自然结构之前进行了预期。与现在的体外研究支持机制，可以具有所有激活功能的设计类似物，但容易获得数量，可以量身定制以避免外围毒性，并且可以具有方便的系数与交付抗体等药物。一种用于Calicheamicin的模型已被证明，将被详细阐述在当前赠款期。关键触发步骤是去障碍烯醇，该操作的设计是涉及几种不同的生物学机制，包括确定的二硫键交换天然产品。结果将是“弹头”的简化模型或可以触发以产生高能量迪尔自由基的aglycone 生理条件。第二个一般触发机制将是基于同一calicheamicin框架，但构象不同调整，船椅环己烷。一组类似的生理兼容过程将被设计到构象触发中。一个与美国医学研究部的合作努力蓝胺将作为选择性DNA裂解剂评估新化合物并安排更活跃的衍生物对交付系统的附件，包括目前正在研究的蓝烷基的单克隆抗体共轭物与天然产品本身。一个重要方面是评估各种DNA递送剂，跟进上一个赠款期内Netropsin的结果。 DNA裂解中的Enediyne的效力非常敏感定位在DNA上，并正确设计递送剂是关键组件。