Synthesis and Study of Amphotericin B Derivatives

描述(申请人提供)：半个多世纪以来，两性霉素一直是治疗危及生命的系统性真菌感染的黄金标准，对这种抗生素的耐药性仍然非常罕见。然而，两性霉素也是剧毒的，因此，由于缺乏疗效，但由于剂量限制的副作用，系统性真菌感染的有效治疗往往被排除在外。由于系统性真菌感染在全球范围内对人类健康构成了日益严重的威胁，一种毒性较低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简单地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体离子通道的自组装，现在可以直接将改善治疗指数的努力集中在更简单的目标上，即更有选择性地结合麦角固醇和胆固醇。为了最大限度地实现这一目标的理性追求，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-小分子相互作用基础上的关键结构-功能关系。总而言之，这些研究将极大地阐明AmB/甾醇相互作用的基本基础，这些相互作用是这种临床上至关重要的抗真菌药物作用机制的核心，产生有希望的候选药物，进一步开发具有改善治疗指数的抗真菌药物，推动基于构建块的高效和灵活的小分子合成平台的继续开发，以及将位点选择性官能化作为获取复杂天然产品的目标衍生物的强大策略。

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.