SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

天然存在的聚醚离子载体(如拉沙洛西德、莫能菌素) 重要的肌力特性。人们认为，这些特性 是这些分子结合和运输能力的函数 跨越生物膜的阳离子。这项提议的目标是 开发强大的方法，通过这些方法，新的人造电离团 具有高度选择性的阳离子结合和传输特性 精心设计和准备的。先前的研究表明，最高的 结合密切相关阳离子的选择性被发现与离子载体 它们的构象灵活性有限。在此应用程序中，我 提出设计和合成一系列新的、吊舱和离子载体 它们在构象上是均一的，因此比大多数 以前研究过电离团。我们将确定三维 这些新的离子载体的结构和结合特性 建立它们的化学结构之间的关系 电离能特性。我们将使用获得的数据来验证 用自由能摄动计算方法预测大气环境质量 新离子载体的电离能特性。这项提议的一个关键目标是 开发一种可靠的计算工具，允许假设 新的电离团的设计将通过计算它们的离子- 绑定或传输属性。这样的工具将允许设计 在耗时的合成之前，具有最佳选择性的新离子载体。

Naturally occurring polyether ionophores (e.g. lasalocid, monensin) have important inotropic properties. It is believed that these properties are a function to the ability of such molecules to bind and transport cations across biological membranes. The objective of this proposal is to develop powerful methods by which new, artificial ionophores which have highly selective cation-binding and transporting properties may be designed and prepared. Previous work has shown that the highest selectivity for binding closely related cations is found with ionophores which have limited conformational flexibility. In this application, I propose designs and syntheses of a series of new, podand ionophores which are conformationally homogeneous nd thus are more rigid than most previously studied ionophores. We will determine the three-dimensional structures and binding properties of these new ionophores in order to establish the relationship between their chemical structures and ionophoric properties. We will use the data obtained to validate a computational method using free energy perturbation for predicting the ionophoric properties of new ionophores. A key goal of this proposal is to develop a reliable computational tool which allows hypothetical designs for new ionophores to be tested by a calculation for their ion- binding or transporting properties. Such a tool would allow the design of optimally selective new ionophores prior to time-consuming synthesis.