Synthesis and Study of Amphotericin B Derivatives

性状（由申请方提供）：两性霉素作为治疗危及生命的全身性真菌感染的金标准已超过半个世纪，对该抗生素的耐药性仍然非常罕见。然而，阿替西霉素也是高毒性的，因此系统性真菌感染的有效治疗常常被排除，不是由于缺乏功效，而是由于剂量限制性副作用。由于全身性真菌感染对全世界人类健康构成了重大且日益严重的威胁，因此毒性较小但同样有效的阿替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，阿替霉素主要通过分别简单地结合麦角固醇和胆固醇来发挥其对酵母和人类细胞的活性。因此，与其试图在酵母细胞与人类细胞中选择性地促进多聚体离子通道的自组装，不如努力改善治疗指数，现在可以直接关注更简单的目标，即更选择性地结合麦角固醇与胆固醇。为了最大限度地实现这一目标的合理追求，我们在此提出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-小分子相互作用的关键结构-功能关系。总的来说，这些研究将基本上阐明AmB/甾醇相互作用的基本基础，这些相互作用是这种临床上重要的抗真菌剂的作用机制的核心，产生有希望的候选物以进一步开发为具有改善的治疗指数的抗真菌剂，驱动用于小分子合成的高效和灵活的基于构件的平台的持续开发，以及先进的位点选择性功能化作为获得复杂天然产物的目标衍生物的有力策略。

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.