Spotlights Cite This: J. Am. Chem. Soc. 2017, 139, 18123−18123
pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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SUZUKI REACTIONS WITH SELECTIVITY AND STEREOSPECIFICITY The Suzuki−Miyaura reaction is the most common reaction in the pharmaceutical industry to connect carbon atoms. Typically the new bond forms between two sp2-hybridized carbons, one functionalized with a boronic ester and the other with a halide. Some suspect this reaction’s popularity contributes to a dearth of suboptimal pharmaceutical leads because the resulting flat molecules appear to frequently bind proteins other than their intended target. In a new Perspective, Jason Rygus and Cathleen Crudden look at ways to use this reaction to connect one sp2 and one sp3 carbon, creating a new bond with specific stereochemistry maintained or inverted from that established in a chiral boronic ester (DOI: 10.1021/jacs.7b08326). Researchers have also developed ways to selectively perform the reaction at only one of several possible sites. The success of these reactions tends to depend highly on the substrate because many approaches use substrate functionality to direct the stereochemical outcome. Future challenges for the field include a better understanding of the reaction mechanism and the role of additives. Developing a stereoselective version of this reaction that connects two sp3 centers would also be highly useful, the authors say. Melissae Fellet, Ph.D.
peroxo species, are notoriously difficult to characterize due to their chemical instability. Now, researchers led by Andrew Borovik demonstrate the use of a protein matrix to stabilize a Cu(II)-hydroperoxo species, revealing important insights into the kinds of hydrogen bonding interactions that are critical to achieving stability (DOI: 10.1021/jacs.7b10452). The protein streptavidin, which tightly binds the small molecule biotin, is used to create an artificial copper protein to stabilize a Cu-hydroperoxido species in solution and in crystal form. Using a biotinylated Cu-complex anchored within the protein, the team finds that the key to stabilization between the protein matrix and the Cu(II)-hydroperoxo species is the donation of hydrogen bonds to the proximal (Cu-bound) oxygen, as they find that H-bonding to only the distal oxygen yields an unstable, reactive variant. This study adds to the growing body of evidence that subtle changes in the environment surrounding a metalloprotein active site can result in substantial changes in stability and reactivity. Christine Herman, Ph.D.
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A GOLDILOCKS PROBE FOR INTRACELLULAR SINGLE-MOLECULE IMAGING A cell-permeable probe that specifically binds its target molecule would enable quantitative single-molecule analysis of intracellular protein dynamics in living cells. While the advent of single-molecule fluorescence technology allows researchers to monitor individual molecules, the technology has been constrained by the lack of suitable probes. Masahiro Ueda, Ytaro Kumagai, Kazuya Kikuchi, and colleagues design a near-infrared fluorescent probe that is hydrophobic enough to pass through the plasma membrane, while being hydrophilic enough to minimize nonspecific binding (DOI: 10.1021/ jacs.7b08262). Their probe specifically binds a tag genetically fused to the protein of interest, in this case the innate immune receptor, Toll-like receptor 4. By combining this probe with a previously developed red fluorescent Halotag system, the team track molecular interactions between the innate receptor and its adaptor molecule, in living cells exposed to bacterial lipopolysaccharide. With multicolor single-molecule imaging, researchers can study dynamic protein−protein interactions to better understand cellular processes at the molecular level. Being able to distinguish signal from noise is critically important for sensitive single-molecule detection. The level of labeling with this new near-infrared probe can be easily titratedwhere fluorescent reporter proteins cannotand avoids spectral overlap with cellular autofluorescence, both promoting a higher signal-to-noise ratio. Sue Min Liu, Ph.D.
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DECODING THE BULLETPROOF VEST OF BACTERIA LINKED WITH COLORECTAL CANCER Some strains of Escherichia coli in the gut make colibactins, a class of molecules linked with DNA damage and colorectal cancer. But these bacteria have a clever defense mechanism that prevents their own DNA from being damaged by the molecules. Steven Bruner, Jason Crawford, and colleagues have figured out the details of this mechanism (DOI: 10.1021/ jacs.7b09971). They show that the bacteria express a protein, ClbS, which makes them resistant to the colibactins by hydrolyzing a key electrophilic cyclopropane ring in the metabolites. This opens the cyclopropane ring and converts it into a nontoxic hydrolysis product. As the cyclopropane plays an important role in colibactin genotoxicity, this ClbS-catalyzed ring-opening provides a way for the bacteria to prevent selfinduced damage. ClbS is also the first cyclopropane hydrolase to be discovered, which could be harnessed to limit DNA damage in the host and have the potential for developing a therapy or preventive strategy for colorectal cancer. Deirdre Lockwood, Ph.D.
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SUBTLE ENVIRONMENTAL CHANGES HAVE HUGE IMPACT ON METALLOPROTEIN REACTIVITY Copper (Cu)-catalyzed oxidation reactions play important roles in both biology and synthetic chemistry. One class of proposed intermediates for these reactions, known as Cu(II)-hydro© 2017 American Chemical Society
Published: December 20, 2017 18123
DOI: 10.1021/jacs.7b13090 J. Am. Chem. Soc. 2017, 139, 18123−18123
