Noteworthy Chemistry

June 22, 2015


These simple luminogens emit efficiently in the solid state. Light emission from organic fluorophores is often significantly quenched when they form aggregates. This aggregation-caused quenching effect is frequently a barrier to practical applications of the fluorophores in fields such as optoelectronics and bioimaging.

Developing fluorogens with aggregation-induced emission (AIE) can help break through the barrier. It is highly desirable to develop AIE luminogens with simple molecular structures and high emission efficiencies. Three AIE fluorogens (see figure) with these features are reported by S. Sasaki, K. Igawa, and G.-i. Konishi* at the Tokyo Institute of Technology, Kyushu University (Fukuoka, Japan), and the Japan Science and Technology Agency.

9-(4-Piperidyl)anthracene (1 in the figure) is nonemissive in organic solvents such as tetrahydrofuran and dimethylformamide; its fluorescence quantum yield (FF) is as low as 0.01. But its solid aggregate emits efficiently, with FF enhanced to 0.71. 

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Mono- and bis(4-piperidyl)anthracenes

Similarly to the monosubstituted anthracene, its disubstituted congeners 9,10- and 1,4-bis(4-piperidyl)anthracenes (2 and 3) show the AIE effect. The FF of solid aggregated 3 is as high as 0.86.

Luminogens 13 have advantages over previously reported AIE systems including simplicity of molecular structure, easy synthetic accessibility, bright solid-state fluorescence, tunable emission colors, and large Stokes shifts. They may thus serve as core chromogens for designing additional functional molecules. (J. Mater. Chem. C DOI: 10.1039/C5TC00946D; Ben Zhong Tang)

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Use ionic liquids to extract DNA from meat. Recent cases of falsely labeled meat products have caused concerns about sanitation and infringement of religious requirements. Current methods for extracting DNA from meat are expensive and require special devices and handling. K. Bica and colleagues at the Vienna University of Technology and the University of Natural Resources and Life Sciences (Tulln, Austria) found that ionic liquids (ILs) are useful for DNA extraction.

The authors’ research groups previously reported that

  • ILs can dissolve biomass;
  • hydrated ILs stabilize DNA; and
  • ILs can enhance the polymerase chain reaction that is used to assign meat origin.

They identified the IL choline hexanoate in a phosphate buffer as the best system for extracting DNA, as measured by how rapidly the DNA is obtained.

The researchers compared the use of the IL with several commercial DNA extraction kits for beef, chicken, pork, and horsemeat. Their method was comparable with the kits for beef, chicken, and pork and superior to the horsemeat kit. DNA extracted by the IL was not contaminated with other biomaterials, and it was stable at room temperature for 20 days. This simple method does not require special techniques or washing and filtration steps. (New J. Chem. DOI: 10.1039/C5NJ00178A, José C. Barros).

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Engineer lysostaphin to combat lethal bacteria. Methicillin-resistant Staphylococcus aureus (MRSA) is a deadly pathogen that is responsible for almost half of all US deaths from drug-resistant bacteria. Given the meager number of antibiotics under development, there is a critical need for new therapeutic options to combat this public health threat.

Lysostaphin is an antibacterial enzyme produced by Staphylococcus simulans, an environmental competitor of S. aureus. Since it was discovered in 1964, lysostaphin has drawn the attention of researchers, pharmaceutical companies, and the medical community because of its extraordinary potency against MRSA in vitro and in vivo. Despite its promising antibacterial properties, lysostaphin is highly immunogenic in a wide array of animal models; and it elicits antidrug antibodies in human subjects. These undesirable immune reactions run the risk of undermining the enzyme’s efficacy and threatening patient safety.

To overcome lysostaphin’s deficiencies, C. Bailey-Kellogg, K. E. Griswold, and co-workers at Dartmouth College (Hanover, NH) designed and developed deimmunized lysostaphin variants that have anti-MRSA activity comparable with wild-type lysostaphin. The researchers used structure-based library design tools to broadly delete putative immunogenic DRB1*0401 restricted T cell epitopes distributed throughout the enzyme’s sequence and structure. Their computational algorithms allowed them to create focused yet diverse variant populations that were amenable to moderate throughput functional screening.

An iterative, directed evolution strategy quickly converged on a highly engineered variant that exhibits significantly reduced antidrug antibody responses following its administration to transgenic mice that contain the human DRB1*0401 MHC II allele. In a recurrent bacteremia model in the same mice, wild-type lysostaphin is effective against only the first cycle of infection, but the deimmunized variant rescues mice from as many as three weekly challenges from a MRSA clinical isolate.

Historically, the immunogenicity and efficacy of deimmunized biologics are assessed in separate, independent models. Here, the authors show longitudinal correlations between antidrug antibody titers and in vivo antibacterial activity. These data provide the first controlled demonstration that depleting T cell epitopes from a biotherapeutic agent enhances efficacy in an immune competent disease model. The broadly applicable nature of the authors’ protein design and deimmunizaiton tools may ultimately aid the rising tide of biologics that entering the development pipeline. (Chem. Biol. DOI:10.1016/j.chembiol.2015.04.017; Xin Su)

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Microbial balance affects sea spray composition. Sea spray aerosol (SSA) particles affect the Earth's climate because they scatter solar radiation and seed cloud formation. These effects can change when ocean phytoplankton blooms release insoluble organic material that mixes with the sea salt particles in the aerosol. Scientists’ understanding of the mechanisms that control the transfer of organic matter from seawater to SSA is limited, and currently it is not possible to predict the organic composition of SSA.

K. A. Prather at the University of California, San Diego, and the Scripps Institution of Oceanography (San Diego) and colleagues at these institutions and the University of Iowa (Iowa City), Colorado State University (Fort Collins), the National Institute of Oceanography and Experimental Geophysics (Trieste, Italy), Xiamen University (China), the University of Wisconsin—Madison, and the University of California, Davis, studied organic matter in SSA produced from a 3400-gal sample of natural seawater in a laboratory wave channel (shown in the figure). 

Laboratory wave channel

The researchers added nutrients to the seawater that spurred two phytoplankton blooms over a 29-day period. They produced SSA by creating breaking waves in the wave channel. The first bloom enriched the aliphatic organic content (including lipids) of submicrometer SSA in proportion to the increasing abundance of phytoplankton, which they tracked by monitoring chlorophyll a concentrations. Ice nucleation in the SSA particles increased concurrently with this bloom.

A second phytoplankton bloom did not enrich organic species in the submicron SSA droplets. Heterotrophic bacteria concentrations, however, were much higher during the second bloom, possibly fed by the lipids from the first bloom. The authors believe that bacterial enzymes degraded the lipids to less active, more soluble species (likely fatty acid salts) that were transferred less efficiently into the submicrometer SSA droplets.

A kinetic model suggests that enhanced SSA organic content depends on a delicate balance between the rate at which phytoplankton produce labile lipids and the rate at which bacterial enzymes degrade these lipids. This helps explain the conflicting results from field studies that investigated the factors that control organic content in SSA and their effects on climate properties. (ACS Cent. Sci. DOI: 10.1021/acscentsci.5b00148; Nancy McGuire)

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Here’s a better way to make 4-amino-5-hydroxypyrimidine. P. T. Le and coauthors at Pfizer Worldwide Medicinal Chemistry (San Diego) and WuXi App Tec (Shanghai) describe several published synthetic routes to 4-amino-5-hydroxypyrimidine (1 in the figure). Many of the routes require the O-demethylation of a 5-methoxy-substituted precursor. 

Improved demethylation route to 4-amino-5-hydroxypyrimidine

One method uses 1-butanethiol with sodium hydride as base, but the yield is low (44%), and 1-butanethiol is extremely malodorous. These drawbacks led the authors to investigate alternative reagents. Sodium methanethiolate (NaSMe) worked well (82% yield), but presented odor problems.

The researchers examined alternative synthetic routes that do not require O-demethylation, but synthetically useful levels of the product were not detected in any of these reactions, even under forcing conditions. The authors then tried the classical demethylating reagent boron tribromide (BBr3), but it gave a sluggish reaction and had a tedious workup. Based on a literature report, methanesulfonic acid and methionine were also tried, but they failed to give any of the desired product.

The best option was to use 1-dodecanethiol with sodium methoxide as base in dimethylformamide (DMF) at 120 ºC. This method gave 1 in 87% yield and 100% purity without the need for chromatographic purification. (Org. Process Res. Dev. DOI: 10.1021/acs.oprd.5b00074; Will Watson)

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