SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

心血管聚醚抗生素的合成

• 批准号: 2215855
• 负责人: WILLIAM C STILL
• 金额: $ 29.37万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2215855
• 关键词: antibiotics; cardiovascular agents; chemical binding; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; ion transport; ionophores; monensin; neurotransmitter receptor

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.

天然存在的聚醚离子载体（例如拉沙洛西、莫能菌素）具有 重要的正性肌力特性。 据信，这些特性 是这些分子结合和运输 阳离子穿过生物膜。 本提案的目的是 开发出强大的方法， 具有高度选择性的阳离子结合和传输特性， 设计和准备。 以前的研究表明， 结合密切相关的阳离子的选择性与离子载体 其具有有限的构象柔性。 在本申请中，我 提出设计和合成一系列新的，podand离子载体， 它们在构象上是均匀的，因此比大多数刚性更大， 以前研究过的离子载体。 我们将确定 这些新的离子载体的结构和结合性质， 建立它们的化学结构之间的关系， 离子体性质。 我们将使用获得的数据来验证 自由能微扰计算方法 新离子载体的离子载体性质。 该提案的一个关键目标是 开发一种可靠的计算工具， 设计新的离子载体，通过计算其离子- 粘合或运输性能。 这样的工具将允许设计 最佳选择性的新的离子载体之前，耗时的合成。