SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

心血管聚醚抗生素的合成

• 批准号: 3338157
• 负责人: WILLIAM C STILL
• 金额: $ 24.4万
• 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 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3338157
• 关键词: Streptomyces; antibiotics; antiinfective agents; cardiovascular agents; chemical structure function; computer simulation; conformation; drug design /synthesis /production; drug screening /evaluation; ethers; ionophores; mathematical model; monensin; muscle relaxants; muscle stimulant

This proposal is directed toward the preparation of effective, new members of the ionophoric polyether antibiotics, a class of molecules which includes compounds with pronounced cardiovascular (inotropic) activity. We have developed a hypothesis which rationalizes the complex stereochemistry of these materials and thus relates their structure to their ion- binding activity. The basis of the hypothesis is that stereochemistry and substitution work together to rigidify the ionophore in the binding conformation to thus enhance ion affinity. If the hypothesis is correct, then it should be possible to design new, structurally related ionophores which retain the activity of the natural ionophores. To test the hypothesis, we will synthesize a series of derivatives of the natural ionophores lasalocid and monensin and measure their binding properties. Some of the derivatives are predicted by our hypothesis to be poor binders of ions ad others are predicted to be good binders. We will also synthesize totally unnatural ionophores whose ion-binding properties should resemble those of the natural polyethers and develop general methods for synthesis and study of natural and unnatural ionophores.

本建议旨在编制有效的、新的 离子型聚醚抗生素的成员，一类 分子，其中包括具有显著 心血管（正性肌力）活动。 我们已经开发出一种 这一假设合理化的复杂立体化学 这些材料，从而将它们的结构与它们的离子- 结合活性。 假设的基础是， 立体化学和取代共同作用， 离子载体的结合构象，从而增强离子 亲和力 如果假设是正确的，那么它应该是可能的。 设计新的，结构相关的离子载体， 天然离子载体的活性。 为了验证这个假设，我们将 合成一系列天然离子载体的衍生物， 并测量它们结合特性。 我们的假设预测了一些衍生品是差的 离子和其它的粘合剂被认为是良好的粘合剂。 我们 也会合成完全非天然的离子载体， 性能应类似于天然聚醚的性能， 开发天然和合成研究的一般方法， 非天然离子载体。