Martin D Burke

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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)
In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to(More)
Amphotericin B (AmB) is a clinically vital antimycotic but is limited by its severe toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells. The leading structural model predicts that the C2' hydroxyl group on the mycosamine(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)
The efficient synthesis of small molecules having many molecular skeletons is an unsolved problem in diversity-oriented synthesis (DOS). We describe the development and application of a synthesis strategy that uses common reaction conditions to transform a collection of similar substrates into a collection of products having distinct molecular skeletons.(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)
Deficiencies of human proteins that protect cells from lipid peroxidation have been linked to many prevalent diseases, including atherosclerosis, neurodegenerative disorders, and cancer. 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)
Aiming to maximally harness the inherent modularity of small molecules, we are pursuing the development of a synthesis strategy based on the iterative cross-coupling (ICC) of bifunctional building blocks representing the substructures that most commonly appear in natural products. In this vein, various combinations of transand cis-olefins are found in many(More)
Amphotericin B (AmB) is the archetype for small molecules that form ion channels in living systems and has recently been shown to replace a missing protein ion transporter and thereby restore physiology in yeast. Molecular modeling studies predict that AmB self-assembles in lipid membranes with the polyol region lining a channel interior that funnels to its(More)
(4e) Zumbuehl, A.; Jeannerat, D.; Martin, S.E.; Sohrmann, M.; Stano, P.; Vigassy, T.; Clark, D.D.; Hussey, S.L.; Peter, M.; Peterson, B.R.; Pretsch, E.; Walde, P.; Carreira, E.M. Angew. Chem. Int. Ed. 2004, 43, 5181-5185. (7b) Baginski, M.; Resat, H.; McCammon, J.A. Mol. Pharmacol. 1997, 52, 560-570. (8) (a) McNamara, C.M.; Box, S.; Crawforth, J.M.;(More)