Synthesis and Study of Amphotericin B Derivatives

这项研究计划的总体目标是开发新的合成策略和方法并使用它们 以原子细节表征两性霉素B(Amb)基于通道的作用机制，从而 使临床上至关重要但毒性也很大的这一治疗指标得以合理优化 抗霉菌剂。 计算机模拟研究预测，添加到天然产品中的某些质子官能团是 对Amb/胆固醇通道的自组装至关重要(这会导致毒性)，但对 AMB/麦角甾醇通道(导致抗真菌活性)，从而导致以下假设： AMB治疗指数的改善可以通过选择性地删除一个或多个 这些质子型官能团。 本研究计划旨在系统地检验这一假说。新的合成策略和方法 将被开发以使附加到两性霉素B上的12个质子型官能团被“删除”， 一次一个。类似于蛋白质科学中的丙氨酸扫描过程，每个 质子官能团的缺失将在一系列生物物理和生物检测中确定。 使用通俗语言的声明： 这种名为“两性霉素”的抗生素是目前治疗生命最有效的药物。 威胁着真菌感染。然而，不幸的是，这种药物有许多毒副作用，这往往限制了它的 功效。这项研究计划旨在更清楚地了解两性霉素是如何起作用的，并尽量减少 这些毒副作用使用有机合成和生物检测相结合的方法。

This overall goal of this research program is to develop new synthesis strategies and methods and use them to characterize the channel-based mechanism of action of amphotericin B (AmB) in atomistic detail, thereby enabling the rational optimization of the therapeutic index of this clinically-vital but also highly toxic antimycotic agent. Computer modeling studies predict that certain protic functional groups appended to the natural product are critical for self-assembly of the AmB/cholesterol channel (which leads to toxicity) but are not critical for the AmB/ergosterol channel (which leads to antifungal activity), thus leading to the following hypothesis: improvements in the therapeutic index of AmB can be achieved via the selective deletion of one or more of these protic functional groups. This research program aims to test this hypothesis systematically. New synthetic strategies and methods will be developed to enable the twelve protic functional groups appended to amphotericin B to be "deleted", one at a time. Analogous to the process of alanine scanning in protein science, the consequences of each protic functional group deletion will be determined in a battery of biophysical and biological assays. Statement in lay language: The antibiotic called "amphotericin" is the most effective medicine currently available for the treatment of life- threatening fungal infections. Unfortunately, however, this drug has many toxic side-effects that often limit its efficacy. This research program aims to understand more clearly how amphotericin works and minimize these toxic side-effects using a combination of organic synthesis and biological assays.