Spotlights pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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MOLECULAR RECOGNITION: UNDERSTANDING WEAK DISPERSION AND HALOGEN-BONDING INTERACTIONS The ability of molecules to bind to one another with enormous specificity is central to nearly all biological processes. For this reason, scientists have long been interested in better understanding the process of molecular recognition and the myriad interactions that take place between molecules to make it possible. Some of the least-well-understood aspects of molecular recognition include weak non-covalent interactions, such as dispersion and halogen-bonding interactions. François Diederich, Markus Reiher, and colleagues reveal new insights into the interactions between a class of receptors, known as alleno-acetylenic cage (ACC) receptors, and small molecules that interact with ACCs via dispersion and halogen bonding(DOI: 10.1021/jacs.7b05461). The team characterizes the elusive conformers of these small molecules at the atomic level both in the solid state and in solution, to show, for example, that the diaxial molecules exhibit dihedral angles that deviate substantially from the commonly accepted value of 180°. Additionally, they perform theoretical calculations finding minimal influence of the host on the innate angles. This is the first study on chiral recognition based purely on shape complementarity, weak dispersion, and halogen-bonding interactions. Christine Herman, Ph.D.
LIGHTING THE WAY FOR COLLOIDAL QUANTUM DOTS Colloidal quantum dots (QDs) have undergone a surge of advancements since their discovery in 1983. In just the past five years, more than 2300 review articles have focused on these unusual nanoparticles. A new Perspective by Jonathan Owen and Louis Brus adds to this collective body, covering the current state of light emission by colloidal inorganic QDs and the importance of chemical synthesis for this critical quality (DOI: 10.1021/ jacs.7b05267). The first colloidal QDs produced nearly four decades ago were plagued with poor crystalline quality, a wide size distribution, and weak luminescence. Since then, advances have been focused on improving the attributes of these particles, aiming for monodispersity, size selectivity, spectral tunability, and brighter luminescence. Most highly emissive colloidal QDs now have a core/shell structure. The reliable luminescence of these particles makes them well suited for displays, with numerous efforts geared toward optimizing core/shell QDs for red and green emission. Another active area is optimizing colloidal QDs for infrared emission in photovoltaics and biomedical uses. Challenges ripe for future study include creating stable and reproducible single photon emitters and QDs that can be excited by electricity for diode emission or laser. The authors suggest that the wealth of research taking place in this relatively new branch of chemistry will lead to further improvements and applications in a broad array of areas. Christen Brownlee
SMALL-MOLECULE ACTIVATION WITHOUT THE NEED FOR TRANSITION METALS The production of carbon-neutral fuels from solar energy requires that small molecules (e.g., CO2) efficiently undergo multi-electron energy-storing redox reactions. These processes require catalysts that are capable of efficiently coupling multiple electron transfers to the cleavage of chemical bonds. While this has traditionally been the job of transition metals, thanks to their intrinsic redox properties and reactivity, recent efforts to forego transition metal ions have emerged. W. Hill Harman and coworkers describe the use of a conjugated, light-element scaffold for the two-electron reduction of multiple energy-relevant small molecules (DOI: 10.1021/jacs.7b06772). The team employs a metal-free scaffold that is an analogue of boranthrene, stabilized by N-heterocyclic carbenes (NHCs). The researchers are drawn to this platform for its synthetic tractability, two-electron redox chemistry, and reactivity with small molecules of interest for chemical fuel applications. The team demonstrates that the platform reacts with O2, CO2 and ethylene and features many of the desirable properties typically associated with transition metal complexes, such as multielectron redox chemistry at mild potentials and reversible ligand binding, pointing in a new direction for small molecule activation. Christine Herman, Ph.D. © 2017 American Chemical Society
REVISING THE CLASSICAL MODEL OF ALLOSTERIC CONTROL Allosteric proteins are the shape shifters of biochemistry. These proteins mediate many cell signaling interactions by opening and closing critical binding sites through a change in conformation. In the canonical view of allostery, an effector such as calcium ion triggers conformational change. Now Lars Konermann and colleagues show that this view may be oversimplified in at least one case (DOI: 10.1021/jacs.7b04380). Using molecular dynamics simulations and hydrogen− deuterium exchange mass spectrometry, they find that allostery in a dimeric signaling protein which binds four calcium ions and two target proteins, is primarily triggered by a labile salt bridge between two residues in the protein itself. This “agitator” destabilizes the protein, eventually leading the protein’s target binding site to close. The effector, calcium, disrupts the agitator’s signaling activity, thereby keeping the target binding site open. Does this alternate allosteric mechanism exist in other proteins as well? The group’s discovery opens up that question, potentially yielding new insights into allosteric proteins involved in disease and drug interactions. Deirdre Lockwood, Ph.D. Published: August 25, 2017 12103
DOI: 10.1021/jacs.7b08937 J. Am. Chem. Soc. 2017, 139, 12103−12104
Journal of the American Chemical Society
Spotlights
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COPPER FINDS MISSING LINK IN ASYMMETRIC COUPLING OF CHIRAL CENTERS Enantiopure building blocks containing adjacent stereocenters are crucial to the synthesis of many pharmaceuticals, natural products, and ligands. A streamlined route to generate such compounds would forge two chiral centers in an enantioselective fashion. However, challenges in promoting the desired carbon− carbon coupling event over competing side reactions, while also controlling the two stereocenters, have made this desirable approach an unsolved problem in organic synthesis. Eswar Bhimireddy and E.J. Corey provide a solution to these challenges based on the reactivity of chiral organocuprates with a unique organic oxidant (DOI: 10.1021/jacs.7b07366). The authors prepare the chiral homocuprates by metalation of chiral lithiated substrates with a copper(I) source. Oxidation of the organocuprates with isopropyl 2,4-dinitrobenzoate generates a transient copper(III) intermediate, which rapidly mediates the stereocontrolled dimerization to form 1,2-diamines, diols, and dithiols. Key to the success of this methodology is the p-electron deficient benzoate oxidant which removes electron density from the organometallic copper species, facilitating the oxidatively induced C−C bond-formation event. The reported work provides efficient access to a variety of enantioenriched building blocks from achiral starting materials, which will likely foster new research in asymmetric synthesis. The results support the idea that decreasing electron density in the participating sigma bonds accelerates reductive elimination. Nicole Camasso, Ph.D.
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CYCLOPEPTIDE SHUTS DOWN HEDGEHOG PATHWAY, OFFERING NEW TOOL TO STUDY AND FIGHT CANCER Using high-throughput screening of cyclic peptides in live cells, Rudi Fasan and colleagues have developed a potent inhibitor of an important biochemical interaction whose aberrant activation is linked with tumor formation (DOI: 10.1021/jacs.7b06087). The Hedgehog signaling pathway is critical to embryonic development and cell differentiation. Abnormal activation of this pathway is also associated with tumor formation in several human cancers. Researchers want to modulate the pathway to better understand its role in cancer development and other diseases. Though one receptor in the pathway has been successfully targeted with inhibitors, it has been more challenging to develop potent inhibitors of the earliest step in the pathway’s activation, known as the Sonic Hedgehog/Patched interaction. Fasan and his team have applied their previously designed peptide cyclization method to develop a potent inhibitor of this interaction. Starting with a target sequence known to bind the Sonic Hedgehog target, they produce a library of recombinantly derived cyclic peptides in bacteria and screen them for improved affinity against the target protein. They eventually isolate an inhibitor capable of potently suppressing activation of the Hedgehog pathway in living cells. This work introduces a potentially general strategy for the development of bioactive cyclopeptide inhibitors of a variety of other challenging protein− protein interactions. Deirdre Lockwood
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DOI: 10.1021/jacs.7b08937 J. Am. Chem. Soc. 2017, 139, 12103−12104
