Noteworthy Chemistry

July 18, 2011

Bioelastomers are potential mechanically active tissue mimics. K. L. Kiick and colleagues at the University of Delaware (Newark) and Brown University (Providence, RI) prepared hydrogels from modified resinlike polypeptides (RLPs) with tunable mechanics for potential applications in vocal fold replacement and other mechanically active tissue technologies. The RLP sequence was modified with β-[tris(hydroxymethyl)phosphine]propionic acid (betaine) to add sites for covalent cross-linking and with the integrin-binding domain GRGDSPG to promote cell adhesion.

The authors formed a series of hydrogels in phosphate-buffered saline solution (20 wt%) at cross-linking amine/betaine ratios of 1:1, 1:2, and 1:4. All RLP elastomers reached equilibrium water uptake within 1 day; water content was >80% even at the 1:4 cross-linking ratio. An examination of the oscillatory shear behavior of the RLP hydrogels showed that

  • the systems gel rapidly;
  • gelation behavior can be controlled by adjusting composition and temperature;
  • the elastomers have substantial elastic stability over a wide range of frequencies; and
  • their shear moduli are tunable from 500 Pa to 10 kPa.

The RLP elastomers exhibit minimal hysteresis and high resiliency under tensile loading over at least three cycles up to ≈200% strain. As anticipated, strength increases and extensibility decreases with an increased degree of cross-linking. Resonance frequency experiments confirmed viscoelastic behavior in frequency ranges relevant to vocal fold technology. (Biomacromolecules 2011, 12, 2302–2310; LaShanda Korley)

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Benzenesulfonamide derivatives show promise against flu. Fusing membranes of enveloped influenza viruses, including the dangerous human H1N1 and avian H5N1 strains, with a host cell is a key step for releasing viral genome into the cell’s cytoplasm. One influenza envelope glycoprotein, hemagglutinin (HA), populates the virus surface and is important for host cell recognition and membrane fusion. Because of this, HA is a useful target for anti-influenza drugs. Recent studies show that human monoclonal antibodies bind to HA, inhibit the fusion process, and have broad-spectrum activity against a variety of HA phenotype group 1 influenza viruses.

A serious limitation of current influenza chemotherapies is the rapid emergence of drug resistance. There is mounting evidence, however, that orally available small-molecule HA inhibitors, particularly those that target specific HA regions, are valuable for treating drug-resistant influenza infections.

G. Tang* and coauthors at Roche R&D Center China and WuXi Apptec (both in Shanghai) identified benzenesulfonamide derivatives as potential inhibitors. They based their strategy on established antiviral structure 1 as the starting point. They synthesized many of these compounds and found that compound 7 has particularly potent antiviral properties.

The authors developed a relatively short synthesis of 7 that starts with nitroaniline 2, which is easily converted to sulfonamide 3. Treating 3 with cis-hydroxycyclohexylamine 4 gives the cis isomer of aniline derivative 5, the desired scaffold. Intermediate 5 is reduced to benzenesulfonamide-2,5-diamine derivative 6, which undergoes a selective Sandmeyer reaction to provide target compound 7.

The authors found that 7 prevents cytopathic effects of influenza A strain H1N1 at a median effective concentration (EC50) of 86 nM. The median concentration (IC50) of 7 to inhibit the hemolysis of chicken red blood cells is 0.25 μM. The results show that 7 inhibits virus fusion by HA binding, which blocks conformation changes in the HA structure.

In vivo studies in CD-1 mice showed that several of the test compounds, including 7, are orally available and have higher in vivo stability and longer terminal half-lives than 1. Viral specificity studies showed that 7 has significant antiviral potency against H1N1, but it is inactive against an HA phenotype group 2 viral strain. The authors suggest that potent HA inhibitors such as 7 with attractive selectivity windows may be useful for combating virulent influenza A pathogens such as the H1N1 and H5N1 strains. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml2000627; W. Jerry Patterson)

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Cigarette butt extracts with copper(I) chloride inhibit corrosion. Cigarette butts contribute to soil and water pollution; recycling them for beneficial use would improve the environment. Aqueous extracts from cigarette butts are mild corrosion inhibitors that have been used for steel oil field tubing. J. Zhao and coauthors at the Tubular Goods Research Center of the Chinese National Petroleum Corp. (Xi’an), Xi’an Jiaotong University, and Xi’an Shiyou University report that adding CuCl improves the inhibition efficiency of cigarette butt extracts

The authors subjected N80 steel to 15% aq HCl in the presence of cigarette butt extracts with and without CuCl. Liquid LC-MS and X-ray photoelectron spectroscopy (XPS) indicated that components of the extracts such as nicotine and quercetin form soluble copper complexes.

Weight-loss and potentiodynamic polarization studies showed that the copper complex acts mainly as an anodic inhibitor, and that the efficiency of inhibition improves somewhat when CuCl is added to the extract. These results were corroborated by electrochemical impedance spectroscopy and electrochemical noise studies. XPS also showed that the copper inhibitor contributes to the formation of a protective coating on N80 steel. Scanning electron microscopy images showed that the copper complexes formed more compact films than without copper and that the films appeared glossy with no evidence of pitting corrosion. (Ind. Eng. Chem. Res. 2011, 50, 7264–7272, José C. Barros)

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Dendritic substituents significantly alter enediyne luminescence. Organic fluorophores are constituents of functional materials with emerging applications in optoelectronics. They are subject, however, to aggregation-induced quenching (AIQ): When the fluorophores organize at the supramolecular level, aggregate formation quenches their light emission. T. Sierra. J. Barluenga, and coauthors at the Universities of Zaragoza and Oviedo (both in Spain) overcame the AIQ problem by designing molecules that generate highly luminescent supramolecular aggregates.

Solutions of enediyne 1 are highly fluorescent, but its crystalline aggregates are nonemissive because of AIQ. When bulky dendrons are attached to the ends of 1, the emission behavior changes drastically. A solution of resulting fluorophore 2 is a weaker emitter than parent form 1, but its aggregates emit efficiently.

Molecules of 2 self-assemble into liquid crystals in the condensed phase and into organogels in appropriate nonpolar solvents. A threefold increase in emission intensity accompanies aggregate formation. This aggregation-induced emission enhancement is probably caused by the restriction of intramolecular rotation of the fluorophoric molecules in the aggregated state. (J. Am. Chem. Soc. 2011, 133, 8110–8113; Ben Zhong Tang)

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What happens during solvent vapor annealing? The conjugated repeat units in poly[2-methoxy-5-(2′-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) make the polymer electrically conductive, and it may have applications in display technologies. Polymer composites with MEH-PPV as a minor component have been studied on substrates. Annealing these membranes for phase separation is a necessary step for making them useful.

Solvent vapor annealing (SVA) is an attractive technique for membrane self-assembly at relatively low temperatures. The composites are exposed to the vapor of an appropriate solvent. The film swells and provides room for MEH-PPV to be mobile at ambient temperature.

J. Vogelsang and co-workers at the University of Texas at Austin explored the rearrangement of the MEH-PPV phase in a poly(methyl methacrylate) (PMMA) matrix during the SVA procedure (Angew. Chem., Int. Ed. 2011, 50, 2257−2261). According to them, the individual MEH-PPV chains “forget” their initial morphology under SVA conditions. Before it is exposed to a solvent atmosphere, the polymer matrix contains folded and unfolded MEH-PPV chains. When the matrix absorbs the vapor of solvents such as toluene and CHCl2, the whole membrane expands. The individual MEH-PPV chains “wander” until they reach thermodynamic stability.

This explanation has been challenged by hypotheses presented by other researchers, including L. Rothberg at the University of Rochester (NY). Rothberg suggests that further investigation is needed to determine whether the behavior of a single molecule represents that of the whole composite. He also argues that Vogelsang’s characterization methods give little information about the polymer’s reorganization at the microscopic level. (Nat. Chem. 2011, 3, 425−426; Sally Peng Li)

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Alkylate primary amines with alcohols under mild conditions. J. Cossy and coauthors at ESPCI ParisTech (Paris) and PCAS (Longjumeau, France) report a remarkably efficient conversion of primary amines to secondary amines with aliphatic alcohols by using a reaction sequence that consists of alcohol oxidation, imine or iminium salt formation, and reduction. This method allows the chemoselective one-pot N-alkylation of amines with a variety of unactivated primary or secondary alcohols.

A key to the process is the selection of the mild 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)–bis(acetoxy)iodobenzene (BAIB) system as the oxidant. Typically, the alcohol substrates are treated with TEMPO–BAIB before the amine and reducing agent NaBH(OAc)3 are added. TEMPO–BAIB oxidation also releases AcOH, which is an effective additive for promoting reductive aminations to the desired monoalkylated amines 1.

Optically active alcohols and amines do not epimerize under the reaction conditions. Alcohol substrates with stereogenic centers in the α- or β-position can be efficiently converted to the corresponding secondary amines 2 and 3.

This sequential one-pot procedure, carried out at room temperature, does not require a transition-metal catalyst. Secondary and tertiary amines can be formed with good functional group tolerance. (Org. Lett. 2011, 13, 3534–3537; W. Jerry Patterson)

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Control fragrance release via host–guest complexation. W. C. E. Schofield and J. P. S. Badyal* at Durham University (UK) used host–guest interactions to control the release of fragrant molecules. Specifically, the authors used the Williams ether synthesis to covalently attach β-cyclodextrin pockets to layers of poly(4-vinylbenzyl chloride) deposited with pulsed plasma technology. They achieved sufficient coverage with β-cyclodextrin host “barrels” at a concentration of ≈20 µM.

The complexation of the vanillin guest molecule within the host β-cyclodextrin was confirmed via IR spectroscopy and microbalance measurements; saturation occurred in <1 min. By using repeated capture–release cycling, the authors determined that the complexation and release of the vanillin occurred with minimal loss of efficiency (<2%). The β-cyclodextrin-modified surface retained significant amounts of vanillin (65% at 8 weeks), whereas only ≈1% of the fragrance remained after 8 weeks in a control nonwoven fabric.

The authors demonstrated this controlled release technique with several essential oils (lavender, sandalwood, jasmine, rosemary, lemon, and vanilla). Sensory evaluation showed that the fragrances were detectable after 8 months. (ACS Appl. Mater. Interfaces 2011, 3, 2061–2056; LaShanda Korley)

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