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Noteworthy Chemistry

March 31, 2014


UN assesses the effects of the Fukushima nuclear accident on wildlife. On March 11, 2011, an earthquake-generated tsunami struck the Fukushima-Daiichi Nuclear Power Station in Japan. The tsunami caused a catastrophic failure and a release of radioactive material that has been rated second in magnitude only to the Chernobyl disaster. The extent of the radiological impact of this event on surrounding wildlife has been a contentious topic.

P. Strand, T. Aono, and coauthors at the Norwegian Radiation Protection Authority (Østerås, Norway), the Norwegian University of Life Sciences (Ås), the National Institute of Radiological Sciences (Chiba, Japan), the Institute for Radioprotection and Nuclear Safety (Saint Paul lez Durance, France), the State Institution Research and Production Association Typhoon (Obninsk, Russian Federation), the University of Groningen (The Netherlands), and Biosphere Impact Studies (Mol, Belgium) evaluated an assessment, overseen by the UN Scientific Committee on the Effects of Atomic Radiation, in which a suite of recently developed techniques was applied to calculate the radiation exposure of regional wildlife. The UN committee compiled monitoring data for the year following the accident; relevant reports and scientific papers provided additional data. Radiation effects were inferred by comparing compiled dose−response relationships.

Radiation exposures were evaluated for the first 3 months after the accident, during which short-lived isotopes played a significant role, and for a later phase (3–12 months), in which exposure was dominated by longer-lived isotopes. Radionuclide concentrations were measured over time and geographic area. Kinetic models were used to calculate time-dependent concentrations in biota. Cumulative doses were determined from dose calculations.

Adult butterflies collected in September 2011 showed more severe abnormalities than those collected in May 2011, indicating deterioration in the population caused by cumulative exposure effects; but dosimetry uncertainties and other confounding factors complicate the interpretation of these observations. The main body of scientific data does not support the appearance of these effects at the dose rates recorded. Reproducing these effects under laboratory conditions required radiation exposures orders of magnitude greater than those observed in the field. Declines in some bird populations and exposures of macroalgae that exceeded corresponding benchmarks also point to possible localized effects.

The team concludes that, because of the short duration of the highest exposure levels, there was likely no damage to the population integrity of plant and animal species. Individual organisms in relatively contaminated areas might have been damaged during the weeks immediately after the accident, especially individuals of radiosensitive and sedentary species living in high-deposition areas.

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Total weighted absorbed dose rates for a large mammal

The figure shows an interpolated map of total weighted absorbed dose rates for a large mammal on March 15 and June 15, 2011. The calculations were based on empirical 131I, 134Cs, and 137Cs soil-deposition data measured in June and July 2011 that were converted to soil concentrations and corrected for radioactive decay to mid-March 2011. During the late phase, individuals of some species, especially mammals, faced potential risks in limited areas. Entire populations are unlikely to suffer significant exposure effects. (Environ. Sci. Technol. Lett., 2014, 1, 198–203; Nancy McGuire)

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Recrystallization produces a less stable compound. A key intermediate in the synthesis of brivanib alaninate, an investigational oncology drug, is 2-methyl-4-fluoro-5-hydroxyindole, which J. A. Pesti and co-workers at Bristol-Myers Squibb (New Brunswick, NJ) prepared via a five-step route from 2,3,4-trinitrobenzene. The final step is a Reissert indole cyclization of 1-(2-fluoro-3-hydroxy-6-nitrophenyl)propan-2-one in which a MeOH solution of this compound is added to aq Na2S2O4. A trace of HCl is added to both solutions because the product is unstable at pH 5–8.

The indole product crystallizes rapidly from the solution. Crystallization isolates the sensitive indole from the other reactants, but it also entrains 200–300 ppm of unreacted substrate. Recrystallization and a clarification step produce brivanib alaninate in >98.0% assay (>99.75 HPLC area%).

The crude drug was stable; but after it was purified, it had to be stored and transported at <8°C. The clarification step mainly removed inorganic sulfur salts that presumably had some antioxidant properties. Attempts to add Na2S2O4 as a stabilizer caused other impurity problems, so cold storage for brivanib alaninate is mandated for now. (Org. Process Res. Dev. 2014, 18, 89–102; Will Watson)

Visualize cancer chemotherapy in vivo with the help of a photostable fluorescent tracker. Developing a controllable drug delivery system that is triggered by the tumor microenvironment is a promising strategy for improving the therapeutic efficacy of anticancer drugs. Because cancer cells have higher intracellular glutathione (GSH) concentrations than normal cells, several GSH-activated prodrugs with disulfide bond linkages have been prepared. Tracking the release of the activated drug in tumors, however, is difficult.

Z. Guo, J. Tang, W. Zhu, and coauthors at East China University of Science and Technology (Shanghai), Zhejiang University (Hangzhou, China), and the University of Bath (UK) developed a near-IR (NIR) fluorescent theranostic prodrug (1). They used it to trace release of the drug and the efficacy of cancer therapy.

The prodrug is a conjugate of a dicyanomethylene-4H-pyran derivative (a NIR dye, red in the figure) and camptothecin (an anticancer drug, blue). These components are connected by a disulfide linker (green) that can be activated. The disulfide bond is cleaved by GSH in tumor cells to release the active drug and turn on NIR emission from the fluorescent dye.

GSH-activated fluorescent prodrug

Prodrug 1 displays excellent tumor-activated cancer therapy with few side effects and great stability to long-term exposure to photoexcitation. (J. Am. Chem. Soc. 2014, 136, 3579–3588; Ben Zhong Tang)

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Now you can “see” hydrogen leaks! Because molecular hydrogen is receiving increasing attention as the next-generation clean energy source, it is necessary to develop improved methods for detecting hydrogen leaks. Traditional hydrogen detectors often rely on expensive, bulky instrumentation; and they do not perform well. Moreover, hydrogen’s low reactivity limits the ability to detect it in the presence of such reactive substances as water vapor and oxygen.

To circumvent these problems and create a practical hydrogen detector, P. Ngene, B. Dam, and coauthors at Delft University of Technology (The Netherlands) and the Free University of Amsterdam built an optical device that allows workers to detect hydrogen with the naked eye with high sensitivity and selectivity.

The authors’ device consists of three layers deposited on a quartz substrate in this order:

  • a thin film of yttrium as the hydrogen reactant,
  • a thin film of palladium as a hydrogenation–dehydrogenation catalyst, and
  • a polytetrafluoroethylene protective coating.

The yttrium layer is highly reflective (see figure, left). When hydrogen is added, it converts the yttrium to semitransparent YH≈2; and then transparent YH3 Interference effects of the hydrides cause a color change (figure, right).

Detection device in the absence (left) and presence (right) of hydrogen

In the hydrogen concentration range from 5 to 1000 ppm, the device displays three colors that correspond to three hydrogenated Y adducts: YH1.9 (deep blue), YH2.1 (gray), and YH3 (light blue). The colors are readily distinguishable by the naked eye.

When the authors alloyed 10% gold into the palladium layer and removed the PTFE coating, the device was made highly resistant toward oxygen and moisture. This variation can detect 1% hydrogen in the presence of 5% oxygen under 97% relative humidity (saturation). The device’s robustness makes it promising for detecting hydrogen in environmental and medical applications. (Adv. Funct. Mater. 2014, 24, Early View; Xin Su

Triptolide targets TAB1 in macrophages. Macrophages are cells that are essential in all stages of the inflammatory process; they produce biologically active components that participate in the positive and negative outcomes of inflammation. Because of their importance to inflammation, macrophages must be tightly regulated.

Many drug candidates target macrophages as a means of controlling inflammatory disease. Among these therapies is triptolide, a diterpene triepoxide that is extracted from the Chinese herb Tripterygium wilfordii; it is used in traditional medicine to treat assorted inflammatory and autoimmune diseases.

Triptolide inhibits the production of pro-inflammatory cytokines and induces macrophage apoptosis, but the mechanisms of how it regulates macrophage function and works as an immunosuppressant are unclear.

P. Shen and colleagues at Nanjing University (China) identified the TAK1-binding protein (TAB1) as a molecular target of triptolide in macrophages. TAB1 is the activator of transforming growth factor-β-activated kinase 1 (TAK1); it activates TAK1 by binding specifically to its catalytic domain. TAK1 controls multiple protein kinase cascades; it is significant in intracellular pathways involved in host of responses to inflammation. The TAK1–TAB1 complex is essential in the mitogen-activated protein kinase (MAPK) pro-inflammatory cellular signaling pathways.

By using several methods, including proteomics, pull-down assays, mass spectrometry, immunofluorescence, isothermal calorimetry, and mouse models, the authors discovered that triptolide binds to TAB1 to prevent the formation of the TAK1–TAB1 complex and therefore to inhibit TAK1 kinase activity. Phosphorylation levels of downstream MAPK kinases that are TAK1 kinase substrates also decrease with triptolide treatment. This cascade results in the downregulation of pro-inflammatory cytokines, which leads to immune suppression.

The authors determined the amino acid residues on TAB1 that are involved in binding and interacting with triptolide. The binding affinity of triptolide to TAB1 correlates strongly with the inhibitory activity of triptolide against MAPK pathway activation. These results provide the specific mechanism of how triptolide inhibits MAPK pathway activation in macrophages and demonstrates the potential of TAB1 as a therapeutic target for inflammatory disease. Because TAK1 kinase is nonredundant in inflammatory and immune response signaling pathways, triptolide can be a selective, potent small-molecule inhibitor of the TAK1-TAB1 complex. (Chem. Biol. 2014, 21, 246–256; Abigail Druck Shudofsky)

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Probe the supramolecular effect in mechanoresponsive materials. W. Weng and co-workers at Xiamen University (China) studied the mechanical activation of supramolecular mechanophore materials. They synthesized a 2-kDa prepolymer of spiropyran end-capped with a diisocyanate and poly(tetrahydrofuran) (PTHF), and then used isocyanate chemistry to functionalize it with a ureidopyrimidinone (UPy).

The supramolecular PTHF-spiropyran materials form phase-separated structures with ≈13-nm domain spacing and exhibit greater mechanical responses than PTHF-spiropyran polyurethane controls. The authors believe that this improvement is most likely the result of UPy dimerization and stacking. When a critical strain is imposed on the system, up to ≈34% of the spiropyran converts to merocyanin, producing a colorimetric change.

Upon deformation, the UPy hard domain stacks fragment and reorient perpendicular to the stretch direction, whereas the PTHF domains exhibit strain-induced crystallization with the PTHF chains aligned in the direction of the strain. The authors suggest that the dynamic UPy associations reinforce the system to allow strain-induced PTHF chain reorganization and a shift in the mechanical response of the incorporated spiropyran. (ACS Macro Lett. 2014, 3, 141–145; LaShanda Korley)

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Oxidize glycerol to lactic acid in a continuous-flow reactor. Glycerol (1) is produced mainly as a byproduct of biodiesel manufacture. It can be turned into various value-added C3 compounds such as lactic acid (2), which is used to produce lactide and poly(lactic acid). Although alkaline hydrothermal oxidation of glycerol is an established green protocol for producing lactic acid, it has the drawbacks of side reactions and prolonged reaction times.

Oxidation of glycerol to lactic acid

To optimize this process, Y. Kimura and colleagues at Okayama University (Japan) switched to a continuous-flow reaction system. This change significantly reduced the reaction time and inhibited the generation of side products.

The authors’ experimental setup consists of three parts: a solution tank equipped with a pump, a continuous-flow reactor, and a cooling water bath. Glycerol in 2 M aq NaOH is pumped into the flow reactor inside a column oven that is maintained at 350 ºC. After a residence time of 2 min, the reaction mixture enters a water bath at 20 ºC, which quenches the reaction.

The conversion of glycerol to lactic acid reaches 90% in the 2-min residence time, much faster than the batch reaction time of 60 min. The authors believe that the rapid temperature shift increases the selectivity to lactic acid by suppressing the formation of formic and acetic acids. (Chem. Lett. 2014, 43, Advance Publication; Xin Su

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