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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)
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)
Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses(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)
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)
Most biologically active small molecules exert their effects via the perturbation of macromolecular targets. 1 There are a few, however, that operate via higher-order mechanisms that lie outside this paradigm. The class of " polyene natural products " 2 is particularly rich with examples. Perhaps most notable is the antifungal heptaene macrolide(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 cytochromes P450 are a multigene super-family of enzymes, existing as multiple forms, which metabolise a wide variety of xenobiotics and endogenous compounds including steroid hormones and arachidonic acid This group of enzymes has a central role in activating and detoxifying chemical carcinogens and anti-cancer drugs (Guengerich, 1988). The major forms(More)
Bronchial asthma and juvenile idiopathic arthritis (JIA) are complex genetic diseases. As both represent chronic inflammatory diseases it is likely that they are at least partially influenced by the same genetic variants. One goal in dissecting the genetics of complex diseases is to identify a genetic risk profile. Therefore it is necessary to genotype(More)