SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

这项建议旨在制定有效的、新的 离子受体聚醚抗生素的一类 包括带有发音的化合物的分子 心血管(变力)活动。我们已经开发出一种 使复杂的立体化学合理化的假说 这些材料，从而将它们的结构与它们的离子- 结合活性。这一假设的基础是 立体化学和取代作用共同作用，使 结合构象中的离子载体从而增强离子 亲和力。如果假设是正确的，那么应该有可能 设计新的、结构相关的电离团，以保持 天然电离团的活性。为了检验这一假设，我们将 合成一系列天然离子载体的衍生物 拉沙洛西和莫能菌素，并测量它们的结合特性。 根据我们的假设，一些衍生品是不合格的。 离子粘结剂和其他粘结剂被预测为良好的粘结剂。我们 也将合成完全非自然的离子载体，其离子结合 性质应类似于天然聚醚和 发展合成和研究天然和有机化合物的一般方法 不自然的电离团。

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.