Spotlights Cite This: J. Am. Chem. Soc. 2018, 140, 2385−2385
pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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SUGAR-LIKE SMALL MOLECULES BUST BACTERIAL BIOFILMS
EXPANDING FRONTIERS IN ORGANIC CHEMISTRY WITH BN ISOSTERES Substitution of carbonaceous arenes with boron and nitrogen, dating back to the 1950s, has afforded access to an array of aromatic heterocycles with unique physical and chemical properties. In a new Perspective, Zachary Giustra and ShihYuan Liu detail recent developments in the synthesis of a subclass of these heterocycles known as azaborines, BN-substituted derivatives of benzene (DOI: 10.1021/jacs.7b09446). Functionalization of 1,2-azaborines, the parent structure of which was isolated almost a decade ago, has developed in many areas: the new synthetic variants show potential as bioactive molecules, ligands in transition metal catalysis, and discrete units in materials chemistry. Novel cyclization reactions have also yielded 1,3- and 1,4-azaborines, and their chemistry is a growing area of research. The authors take two small detours to discuss progress in the synthesis of related BN-naphthalenes, which may pave the way for their applications in medicine and catalysis. Notwithstanding advancements in the chemical and functional development of azaborines, the authors underline the need for additional synthetic methodologies to spur progress in this field. With an eye toward the future, they note that azaborines may hold value as C-B-N synthons, emphasizing the unexplored versatility of these heterocycles in organic chemistry. Katie Meihaus, Ph.D.
For people with compromised immune systems or cystic fibrosis, infection with the bacteria Pseudomonas aeruginosa can be very dangerous. The microbe tends to form biofilms that resist treatment with antibiotics, leading to pneumonia, sepsis, and lung damage. Now Alexander Titz and colleagues have developed two classes of small molecules, cinnamides and sulfonamides, that could help stem these infections (DOI: 10.1021/jacs.7b11133). The compounds inhibit LecB, a carbohydrate-binding protein that the bacteria need to make the protective biofilm. The researchers show that these compounds, whose structures resemble carbohydrates, are highly selective for LecB and block biofilm formation in vitro. They also show low toxicity and high stability. Finally, the team has successfully administered the small molecules orally in mice, with good delivery to the whole body based on their concentrations in plasma and effective excretion based on their levels in urine. This new class of glycomimetic inhibitors is an improvement over previously developed multivalent LecB inhibitors that can have the undesirable effect of stimulating biofilm formation. Their oral bioavailability suggests that they have potential for development as drugs to treat infections caused by P. aeruginosa. Deirdre Lockwood, Ph.D.
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INTERSECTING POTENTIAL ENERGY SURFACES HELP EXPLAIN ADIABATIC DISSOCIATION Adiabatic potential energy surfaces (PESs) are the classic method to analyze chemical reactions. The approach is derived from Born−Oppenheimer approximations, which assume that nuclear and electronic motions in a molecule can be separated, resulting in simpler computation of a molecule’s energy and its wave function. However, the approximation breaks down in polyatomic molecules, where multiple PESs are degenerate and thus can result in a conical intersection. Conical intersections play an essential role in key non-adiabatic processes, but their effects on adiabatic dynamics are often disregarded. David Yarkony, Daiqian Xie, Hua Guo, and colleagues look at the hydroxymethyl radical to take into account the effect of a conical intersection on adiabatic dissociation (DOI: 10.1021/ jacs.7b11489). They find that rupture of the O−H bond on the ground state is significantly affected by this conical intersection with the electronically excited state along the dissociation path, even at energies significantly below the intersection. Treating such processes by the single-state Born−Oppenheimer approximation results in an incorrect wave function, and thus wrong dissociation lifetimes or product state distributions. These results suggest that a proper treatment of adiabatic dissociation should incorporate the effects of the conical intersection. Dalia Yablon, Ph.D.
COMPARING DRUG CARRIERS TO DELIVER A TUMOR-KILLING PUNCH
To assess two different forms of drug carriers for treating cancer, Dario Neri and co-workers have directly compared the in vivo performance of a monoclonal antibody with that of a small molecule, both conjugated to the same anti-cancer drug, with surprising results (DOI: 10.1021/jacs.7b13361). Targeted drug delivery is of great interest because being able to deliver drugs directly to the affected tissues provides many benefits, including more efficient killing of cancer cells, lower doses of toxic drugs required, and reduced adverse off-target effects associated with traditional anti-cancer therapies. Drug− antibody conjugates are potentially useful for this purpose and have demonstrated real utility in the clinic. A conceptually alternative method would be the use of small molecules that bind selectively to proteins overexpressed in tumors. Neri’s team directly compares the two approaches for cancer therapy. Both carriers tested bind to a protein overexpressed in renal cell carcinoma with high specificity. The researchers find that, while drugs delivered by both carriers reduce tumor mass, the drugcarrying small molecule is slightly less efficacious despite displaying higher and more tumor-specific uptake than the antibody carrier. The drug-carrying small molecule is also cleared much faster from the circulation than the antibody. This work sheds light on the development of new drug delivery conjugates. Sue Min Liu, Ph.D. © 2018 American Chemical Society
Published: February 21, 2018 2385
DOI: 10.1021/jacs.8b01655 J. Am. Chem. Soc. 2018, 140, 2385−2385
