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Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily(More)
Most of the functional molecules found in living systems, including most " small molecules " , are biosynthesized via iterative coupling of bifunctional building blocks. Polypeptides, 1 oligonucle-otides, 2 and to a growing extent oligosaccharides 3 can be similarly prepared in the laboratory via simple oligomerization of suitably protected versions of(More)
Deficiencies of human proteins that protect cells from lipid peroxidation have been linked to many prevalent diseases, including atherosclerosis, neurodegenerative disorders, and cancer. [1] Remarkably, some species of bacteria have the ability to thrive in environments of extreme oxidative stress, which has been attributed to the presence of specialized(More)
Due to its sensitivity to most synthetic reagents, it is typically necessary to introduce the boronic acid functional group just prior to its utilization. Overcoming this important limitation, we herein report that air- and chromatographically stable MIDA boronates are compatible with a wide range of common reagents which enables the multistep synthesis of(More)
Stimulated by the substantial challenge of synthesizing the complex and sensitive stereogenic allene-containing core of (-)-peridinin, the first stereocontrolled coupling of haloallenes with boronic acids has been achieved. This new method and the principles that emerged during its development stand to enable the more efficient and flexible preparation of a(More)
The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent(More)
For over 50 years, amphotericin has remained the powerful but highly toxic last line of defense in treating life-threatening fungal infections in humans with minimal development of microbial resistance. Understanding how this small molecule kills yeast is thus critical for guiding development of derivatives with an improved therapeutic index and other(More)
Lack of efficient access to collections of synthetic compounds that have skeletal diversity is a key bottleneck in the small-molecule discovery process. We report a synthesis strategy that involves transforming substrates with different appendages that pre-encode skeletal information, named sigma elements, into products that have different skeletons with(More)
Amphotericin B is the archetype for small molecules that form transmembrane ion channels. However, despite extensive study for more than five decades, even the most basic features of this channel structure and its contributions to the antifungal activities of this natural product have remained unclear. We herein report that a powerful series of functional(More)
The leading model for the antifungal action of amphotericin B (AmB, 1) involves its self-assembly into a membrane-spanning ion channel. 1 This natural product thus represents a potential prototype for small molecules with the capacity to perform ion channel-like functions in living systems. Efforts to harness this potential and/or improve the notoriously(More)