Spotlights pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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ILLUMINATING THE MOVES OF A DEFENDER AGAINST ALZHEIMER’S DISEASE The compound epigallocatechin gallate (EGCG), derived from green tea, is one of the most promising small molecules for developing Alzheimer’s therapies because it blocks the formation of neurotoxic amyloid plaques associated with the disease. Exactly how it does this, however, is still largely unclear. Giuseppe Melacini and colleagues shed new light on the mechanism of EGCG’s action with a combination of peptidebased NMR, various spectroscopic methods, and more (DOI: 10.1021/jacs.7b05012). Amyloid beta plaques form when certain amyloid peptide monomers associate with one another to form oligomers, eventually becoming larger, toxic protofibrils. EGCG can interfere with the formation of amyloid plaques by preventing these monomers from aggregating into protofibrils. Many aspects of this mechanism are “invisible” to NMR because the protofibrils are too large for the method to detect. Melacini and his team use dark-state exchange saturation transfer NMR spectroscopy, combined with fluorescence and other methods, to dissect the mechanism. They propose that EGCG remodels the oligomers by binding them at multiple binding sites, making the oligomers less exposed to solvent. This limits their contact with monomers and their ability to form toxic fibrils. The study tackles fundamental questions related to the mechanism of Alzheimer’s disease and presents an effective tool for investigating lowmolecular-weight amyloid inhibitors. Deirdre Lockwood, Ph.D.
EXPANDING THE ASYMMETRIC REDUCTION OF TETRASUBSTITUTED ALKENES Substrates bearing vicinal stereocenters serve as valuable chiral building blocks in synthetic chemistry and in the preparation of many biologically active compounds. Scientists have recently developed a strategy to directly access these important motifs via the asymmetric hydrogenation of tetrasubstituted olefins (AHTO). In their Perspective, Robert Kargbo and colleagues discuss recent advances in AHTO and the remaining opportunities for future developments in this emerging field (DOI: 10.1021/jacs.7b07188). Developing asymmetric protocols for the hydrogenation of tetrasubstituted alkenes is a significant synthetic challenge due to difficulties in controlling two adjacent stereocenters and balancing steric and electronic biases of the substrates. Zhou and Buchwald first demonstrated the potential of this approach with their critical breakthroughs in the hydrogenation of functionalized and unfunctionalized olefins, respectively. More recent advances in the literature have shown that ruthenium, iridium, and rhodium catalysts efficiently promote these transformations, with chiral diphosphines often being employed as ligands. However, the chiral catalyst to substrate specificity in these methods severely limits their broad utility. Identifying catalytic systems that overcome this inherent limitation will be critical in the next stage of AHTO discoveries. Nicole Camasso, Ph.D.
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MIMICKING CELL MEMBRANES WITH ARTIFICIAL TRANSMEMBRANE SIGNAL TRANSDUCTION Nicholas H. Williams, Christopher Hunter, and colleagues report a system comprised of lipid bilayer vesicles that undergo controlled release of molecular cargo in response to a change in pH in the external environment (DOI: 10.1021/jacs.7b07747). Cells engage with the outside world through transmembrane proteins that are able to sense chemical signals in their environment. The interactions cause a cascade of intramolecular interactions within the cell, in a process known as signal transduction, for which the end result is often the release of molecules into the external environment. In an attempt to mimic this complex biological phenomenon in a synthetic chemical system, the team sets out to create an artificial transmembrane signal transduction system. They demonstrate how the synthetic signal transducer embedded within the lipid bilayer membrane is able to act as a switchable catalyst, initiating the formation of surfactant molecules inside the vesicles in response to the external pH change, ultimately leading to the release of an encapsulated hydrophilic cargo. The work has important implications in the design of synthetic molecular delivery systems, such as drug delivery systems that can undergo triggered release of molecular cargo. Christine Herman, Ph.D.
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TRACKING HYDROGEN DEEP IN THE EARTH’S MANTLE The movement of water from the Earth’s crust to its deeper layers affects the chemical properties of mantle minerals as well as the geochemical evolution of the planet. Under high-pressure conditions, the asymmetric hydroxyl bonds present in some minerals form a symmetric configuration in which H is present at the center of the two O atoms. This placement improves their thermal stability and makes it possible for water-bearing minerals to be present deeper in the earth. However, how H is recycled from the mantle is unclear. To investigate this phenomenon, Qingyang Hu and coworkers use a combination of modeling and experiments to better understand the dehydrogenation mechanism of one such water-bearing mineral, FeO2H (DOI: 10.1021/jacs.7b06528). Their work reveals that at high temperature and under high pressure, about half the O−H bonds rupture, releasing ∼50% of this mineral’s hydrogen content as it transitions to a pyrite-type phase. The authors speculate that the hydrated minerals might concentrate in the oceanic crust, from which they descend to the mantle, and then stabilize there by releasing hydrogen. The findings have significant implications for chemistry occurring in the Earth’s deeper layers. Christen Brownlee © 2017 American Chemical Society
Published: September 27, 2017 13249
DOI: 10.1021/jacs.7b09963 J. Am. Chem. Soc. 2017, 139, 13249−13249
