Synthesis and Study of Amphotericin B Derivatives

描述（由申请人提供）：两性霉素作为治疗危及生命的系统性真菌感染的金标准已有半个多世纪，对这种抗生素的耐药性仍然非常罕见。然而，两性霉素也有剧毒，因此对全身性真菌感染的有效治疗常常被排除在外，不是因为缺乏疗效，而是因为剂量有限的副作用。由于全身性真菌感染对全世界人类健康构成了日益严重的重大威胁，一种毒性较小但同样有效的两性霉素衍生物将产生重大影响。最近，与广泛接受的通道模型相反，我们发现两性霉素主要通过分别结合麦角甾醇和胆固醇来发挥其对酵母和人类细胞的活性。因此，与其试图在酵母和人类细胞中选择性地促进多聚离子通道的自组装，不如将改善治疗指数的努力直接集中在更有选择性地结合麦角甾醇和胆固醇的更简单的目标上。为了最大限度地实现这一目标，我们在此建议利用有机合成的力量来系统地表征这种非常罕见的小分子-小分子相互作用背后的关键结构-功能关系。总的来说，这些研究将极大地阐明AmB/甾醇相互作用的基本基础，这是这种临床重要抗真菌药物作用机制的核心，为进一步开发具有改进治疗指数的抗真菌药物提供有希望的候选药物，推动高效灵活的基于构建块的小分子合成平台的持续发展。以及先进的位点选择性功能化作为一种强大的策略，以获得复杂的天然产物的靶向衍生物。

DESCRIPTION (provided by applicant): Amphotericin has served as the gold standard for treatment of life-threatening systemic fungal infections for more than half a century, and resistance to this antibiotic remains exceptionally rare. However, amphotericin is also highly toxic, and thus the effective treatment of systemic fungal infections is all too often precluded, nt by a lack of efficacy, but by dose-limiting side effects. Because systemic fungal infections represent a major and growing threat to human health worldwide, a less toxic but equally effective amphotericin derivative stands to have a major impact. Recently, in contrast to the widely accepted channel model, we discovered that amphotericin primarily exerts its activity against yeast and human cells by simply binding ergosterol and cholesterol, respectively. Thus, rather than trying to promote the self-assembly of multimeric ion channels selectively in yeast vs. human cells, efforts toward an improved therapeutic index can now focus directly on the much simpler goal of more selectively binding ergosterol vs. cholesterol. To maximally enable the rational pursuit of this objective, we herein propose to harness the power of organic synthesis to systematically characterize the key structure-function relationships that underlie thi very rare type of small molecule-small molecule interaction. Collectively, these studies will substantially illuminate the fundamental underpinnings of AmB/sterol interactions that are central to the mechanism of action of this clinically vital antifungal agent, generate promising candidates for further development as antifungal agents with an improved therapeutic index, drive the continued development of a highly efficient and flexible building block-based platform for small molecule synthesis, as well as advance site-selective functionalizations as a powerful strategy for accessing targeted derivatives of complex natural products.