Noteworthy Chemistry

February 24, 2014

Make antimicrobial silicon chips via “click” immobilization. Tet213 is a potent, inexpensive antimicrobial peptide. It can be incorporated into substrates by physical adsorption, but its burst release resulting from this method cannot be controlled. Covalent immobilization may solve the problem, but harsh reactions used to attach Tet213 may deactivate the drug.

L. Ren, Y. Wang, and colleagues at the South China University of Technology (Guangzhou) developed a benign chemical method for grafting Tet123 onto a substrate without losing bioactivity. They used Cu(I)-catalyzed azide–alkyne cycloaddition, the best known click reaction, to functionalize silicon wafers with the Tet213 peptide. They chose silicon wafers because they are widely used substrates in the manufacture of bioelectronic chips and medical devices.

The click reaction proceeds under mild conditions and does not contaminate the wafers with harmful substances. The functionalized wafers work well as antibiotic agents: In 2.5 h, they inhibit 99.3% of Staphylococcus aureus and 95.0% of Escherichia coli bacteria applied to them. The authors demonstrated the wafers’ biocompatibility by exposing rat bone mesenchymal stem cells to them with little resultant cytotoxicity. (Chem. Commun. 2014, 50, 975–977; Ben Zhong Tang)

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This wound sealant can be dissolved to allow re-exposure. Hydrogels are one type of biomaterials that are used as wound sealants. There are, however, no reports of using them for emergency care. M. W. Grinstaff and co-workers at Boston University hypothesized that the reversible thiol–thioester exchange reaction could be used to produce hydrogels that could seal a wound and be dissolved later for surgical treatment of the wound.

The authors prepared PEG-LysSH hydrogels via the room-temperature reaction between lysinethiol (LysSH)–based dendron 1 and poly(ethylene glycol) (PEG) derivative 2 (see figure). The freshly prepared hydrogel (3) is directly applied to a wound. The material exhibits suitable mechanical and viscoelastic properties even after it absorbs fluids from the wound. Cytotoxicity and immunogenicity studies showed that the material is safe. The gel can be dissolved by adding L -cysteine methyl ester (4) or by thiol–thiolate exchange.

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Wound-sealing hydrogel starting materials, structure, and dissolution procedure

As an example, the authors tested the material ex vivo for sealing a 2.5-mm diam hole in a bovine jugular vein. They filled the vein with phosphate-buffered saline solution under ≈250 mm Hg pressure (twice the normal arterial blood pressure). The gel sealed the wound, sustained the pressure without leaks, and was later dissolved. This method may also be used to control re-exposure of the wound during surgical care. (Angew. Chem., Int. Ed. 2013, 52, 14070–14074; José C. Barros).

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Allow time for the active catalyst to form. L. Lefort and coauthors at DSM Innovative Synthesis BV (Geleen, The Netherlands), DSM Fine Chemicals Austria (Linz), GlaxoSmithKline (Stevenage, UK), and Actelion Pharmaceuticals (Allschwill, Switzerland) describe their efforts to develop efficient, scalable hydrogenation and transfer hydrogenation processes for an asymmetric reduction reaction. The substrate was a dihydroisoquinoline intermediate in the production of almorexant, an efficient antagonist for orexin receptors.

Low conversions and low enantioselectivity plagued attempts to reduce catalyst loadings to make the process less costly. When the authors screened prospective catalysts in a high-throughput A96 parallel plate reactor, an iridium-based TaniaPhos T002-1 ligand system with iodine as a promoter gave good results (94% ee). {TaniaPhos T002-1 is (RP)-1-dicyclohexylphosphino-2-[(R)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]ferrocene.}

During further development, however, the authors obtained inconsistent results that were caused by the variable amount of time it took to prepare the catalyst. In the 96-well plate reactor, there was an almost inevitable ≈1-h delay until the iodine was added to the ligand and metal; but in subsequent development, the time was reduced to ≈20 min. Allowing a 1-h incubation time for metal and ligand before iodine addition gave reproducible results when the reaction was scaled up (10 batches of 750 kg substrate). (Org. Process Res. Dev. 2013, 17, 1531–1539; Will Watson)

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Here is a robust catalyst for hydrogen-fueled cars. Hydrogen-powered vehicles are receiving a lot of attention from the automotive industry. By the end of 2013, several companies announced prototypical hydrogen fuel cell vehicles. Despite increasing market demands, however, hydrogen fuel cell vehicles still face technical challenges to reliable, practical performance.

One critical problem is the instability of electrocatalysts in hydrogen-membrane fuel cells that leads to degradation, activity loss, and other factors. To mitigate this problem, V. Ramani and coauthors at the Illinois Institute of Technology (Chicago) and Nissan Technical Center North America (Farmington Hills, MI) developed a stable platinum composite that can be used as an electrocatalyst.

Current electrocatalysts consist of active nanosized platinum on carbon- or oxide-based supports. They are subject to platinum dissolution and support corrosion during vehicle operation. The authors prepared a support material consisting of titanium–ruthenium (Ti/Ru 1:1 mol/mol) mixed oxides (TROs) by precipitating ruthenium hydroxides on TiO2 nanopowder, then calcining the mixture at 450 ºC. Platinum nanoparticles were reductively deposited onto the TRO support from a platinum salt.

The authors tested the electrochemical stability of the Pt/TRO catalyst system against protocols designed to simulate processes in the operation of hydrogen vehicles. The Pt/TRO catalyst was more stable than the benchmark catalyst (platinum supported on high surface area carbon [Pt/HSAC]) in ex situ rotating-disk electrode and in situ membrane electrode assembly settings.

Although ruthenium is more expensive than carbon, cost-modeling analysis indicates that platinum constitutes >95% of the catalyst cost and because of its advantageous performance, the Pt/TRO catalyst would be more economical than Pt/HSAC. (Proc. Natl. Acad. Sci. USA 2014, 111, 45–50; Xin Su)

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Adding salt induces gelation-enhanced emission. G. Zou, X.-J. Liang, and coauthors at the National Center for Nanoscience and Technology (Beijing) and the Chinese Academy of Sciences (Lanzhou) developed a functional small-molecule gelator that can form a luminescent hydrogel. Specifically, they designed and synthesized a gelator that contains tetraphenylethylene (TPE), which exhibits enhanced luminescence upon aggregation, and a salt-responsive peptide, Q19, which is derived from a sequence that forms fibrils in the presence of salts.

TPE-Q19 forms gels when >0.3 wt% aq NaCl is added. Temperature, pH, and solvent changes do not affect gelation. Of particular importance in the design of the gelator is a hydrophilic amino acid sequence that tips the balance from precipitation to gelation.

As the NaCl content increases from 0 to 1.5 M, the TPE fluorescence intensity at 465 nm increases rapidly. The gelation rate is influenced by salt concentration: Gelation occurs within 10 min at 1.0–1.5 M NaCl, compared with >1 h at millimolar salt concentrations for the same TPE-Q19 concentration.

The authors also explored the gelation and enhanced emission mechanisms. They determined that the TPE unit participates in the structural formation of the gel and the Q19 fragment inhibits TPE rotation and enhances fluorescence (similarly to aggregation-induced emission).

The mechanically robust hydrogels have a highly entangled network structure. Enzymatic hydrolysis of the gels induces a gel-to-sol transition; but emission intensity is maintained, most likely because of the structure of the hydrolytic fragments and the position of the TPE units within the gel. (ACS Appl. Mater. Interfaces 2014, 6, 757–762; LaShanda Korley)

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This polymerase that can detect N6-methyladenosine. The most abundant messenger RNA (mRNA) modification, N6-methyladenosine (m6A, 1 [Figure 1]), is also abundant in transfer RNA (tRNA), ribosomal RNA (rRNA), and small nuclear RNA (snRNA). m6A is of clinical significance because it can be demethylated by fat mass and obesity-associated protein, which is encoded from the obesity risk gene FTO. It is challenging to locate m6A modifications precisely in RNAs, and this difficulty hinders the understanding of m6A’s function.

Current sequencing methods make it possible to roughly characterize adenine methylation, but locating specific methylated adenines requires arduous digestion analysis. Because polymerases can be sterically sensitive, E. T. Kool and co-workers at Stanford University (CA) postulated that a polymerase that is selective against m6A might be used as a site-specific probe for adenine methylation.

The researchers screened several enzymes with reverse transcriptase activity by testing their ability to incorporate adenine instead of m6A in an RNA template. They found that recombinant Thermus thermophilus DNA polymerase I (Tth pol) exhibited outstanding selectivity for adenine over m6A (61% vs 15%) in radiolabeled DNA primer extension.

Figure 2 shows the identification of methylated adenine (A) sites in human rRNA. Primers were designed to probe for m6A at three sites in rRNA. Incorporation at these sites by Tth pol was compared with incorporation by Tth pol at known nonmethylated control sites and with incorporation by nonselective avian myeloblastosis virus reverse transcriptase.

N6-methyladenosine structure
Identification of methylated adenine sites in human rRNA

The selectivity of Tth pol ranged from 4- to 18-fold when it was subjected to various sequence contexts. The authors also demonstrated that the polymerase can quantitatively evaluate the degree of methylation at specific sites in RNAs. More importantly, Tth pol can be used to probe m6A in RNAs extracted from mammalian cells and in a cellularly expressed mRNA. This study identified an enzyme that can discriminate m6A from adenine and expands the m6A analysis toolbox. (J. Am. Chem. Soc. 2013, 135, 19079–19082; Xin Su)

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A decision-support framework helps develop energy strategies. Implementing the 2013 US Climate Action Plan requires a national strategy for energy generation and delivery that is based on scientifically sound evidence and stakeholder decisions. Research suggests that effective decision-support systems help decision-makers make more thoughtful tradeoffs among objectives and strike a better balance between intuitive and analytic reasoning.

D. L. Bessette*, J. Arvai, and V. Campbell-Arvai at the University of Calgary (AB) and Decision Research (Eugene, OR) developed and tested a decision-support framework that draws on two established methods: structured decision-making (SDM) and portfolio analysis. SDM, a time- and resource-intensive approach, breaks complex decisions into components, allowing an attribute-by-attribute evaluation of a complex technical issue. Portfolio analysis is a rapid, intuitive holistic approach that ranks options on the basis of real-world constraints.

As their test case, the authors chose an initiative at Michigan State University (East Lansing) to generate a new long-term plan for the university's power-generating system. The study participants, 182 randomly selected college juniors and seniors, used an online dashboard to work with an interactive energy system model tailored to the MSU campus with the assistance of an onsite facilitator.

Two groups of participants built their own portfolios, whereas two other groups did not. All of the participants evaluated six energy portfolios on how effectively they achieved six objectives (for the first two groups, these strategies included portfolios that they had designed themselves). They then performed holistic ranking (portfolio analysis) and attribute-weighting (SDM) procedures. Two groups (one with self-designed portfolios and one without) performed the holistic analysis first; the other two groups started with the attribute weighting.

The order in which participants engaged with the holistic-ranking and attribute-weighting exercises had no significant effect on any of the self-reported responses with respect to adequacy of information provided and ease of use of the system. A review of the participants’ decisions, however, indicated that the group that built its own portfolios and performed attribute weighting before holistic ranking produced the most internally consistent choices. The rankings more closely matched the preference orders implied by attribute weights.

Participants consistently gave the highest rankings to portfolios that contained nuclear power and the lowest rankings to portfolios that relied on coal and natural gas. The most expensive portfolios with the least greenhouse gas and particulate air emissions were consistently preferred over the least expensive higher-emitting portfolios. Emission reduction took precedence over cost, job creation, and land use.

The authors are conducting follow-up studies to investigate whether this ranking holds when a more diverse population is surveyed and when the entire survey is conducted online in the absence of a facilitator. (Environ. Sci. Technol. 2014, 48, 1401–1408, Nancy McGuire

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