Noteworthy Chemistry

January 14, 2013

These two compounds may replace a withdrawn antidepressant. Dual norepinephrine and dopamine reuptake inhibitors (NDRIs) such as nomifensine (1) are used to treat depression. Because of severe side effects, however, nomifensine was withdrawn from the market.

D. G. Brown at AstraZeneca Pharmaceuticals (Wilmington, DE), C. A. Hurley at Argenta (Harlow, UK), and 29 colleagues set out to find antidepressant NDRIs that do not cause major side effects. Because of nomifensine’s NDRI properties, the authors used it as the starting point of their structure–activity relationship analysis.

On the basis of published reports, the authors deduced that the aniline moiety in 1 is not important for activity and that the fused aromatic ring can be replaced by a single heterocyclic ring. Of the several candidates they investigated, 2,3,4,7-tetrahydro-1H-azepine and piperidine had the greatest activity.

The authors synthesized a series of analogues with various substituents on the two heterocycles and then tested the analogues’ inhibition properties. Compounds 2 and 3 emerged as the most promising for norepinephrine and dopamine reuptake inhibition. The compounds were tested on rats for their antidepressant properties and displayed behavioral profiles similar to nomifensine.

These results show that compounds 2 and 3 are potential drugs for treating depression. Further investigation into clinical doses and side effects is needed. (ACS Med. Chem. Lett., 2013, 4, 46–51, Chaya Pooput)

Use zeolites to break down lignin to gasoline. Lignin is one of the major sources of biomass, and it is a promising precursor for gasoline-range hydrocarbons. It is difficult, however, to refine because of its complexity and low bio-oil yield. To take advantage of lignin’s aromatic-rich structure, H. Ben and A. J. Ragauskas* at Georgia Tech (Atlanta) developed a one-step process that uses zeolites to pyrolyze lignin to simple aliphatic and aromatic liquids.

The authors heated lignin in the presence of five zeolites with different frameworks: ZSM-5, Y, β, ferrierite, and mordenite. In each case, the zeolite was activated, and then a 1:1 w/w mixture of lignin and the zeolite was pyrolyzed under nitrogen at 600 °C. The yield of char (45−55%) was usually greater when a zeolite was added to lignin than with lignin alone. They characterized the pyrolyzed oils by using various NMR techniques.

The ratio of heavy to light oils depended on zeolite structure, as did the degree of formation of polyaromatics. The zeolite additives promoted dehydration and decarboxylation, which make these products suitable for fuel use. Zeolites Y and β yielded gasoline-range liquids, whereas ZSM-5, ferrierite, and mordenite decomposed carboxyl groups to a greater extent and produced heavier, low-acidity biofuel candidates. (RSC Adv. 2012, 2, 12892–12898; Xin Su)

Optimize a Vilsmeier formylation reaction. The Vilsmeier formylation of 4-fluoro-1-(tetraacetylglucosidyl)indole under standard conditions (3 equiv POCl3 and 6 equiv DMF at 90 °C) produced significant amounts of the 2,3-diformylated compound as an impurity. Optimization studies carried out by X. Li and co-workers at Janssen Research and Development (Spring House, PA) showed that ≥2.5 equiv POCl3 is needed for a fast reaction, but the reaction can be carried out at 30–40 °C, which prevents the diformylation reaction.

Quenching the reaction mixture is extremely exothermic and must be carried out by carefully adding the reaction mixture to 3 M aq NaOAc solution at 30–40 °C. Under these conditions, the desired 3-formyl product can be isolated in quantitative yield. (Org. Process Res. Dev. 2012, 16, 1727–1732; Will Watson)

These olefin metathesis catalysts are easy to separate. The development of Grubbs and Hoveyda–Grubbs ruthenium catalysts contributed to the success of the useful olefin metathesis reaction, but the difficulty of removing heavy-metal impurities from the products is a drawback to its use in the pharmaceutical industry. Most separation methods require the use of scavengers or multiple chromatography cycles.

K. Skowerski, K. Grela, and coauthors at Apeiron Synthesis (Wrocław, Poland) and Warsaw University developed metathesis catalysts 13 that contain quaternary ammonium groups attached to N-heterocyclic carbenes. The “quad” groups make it easy to remove the catalysts from reaction mixture. (Mes is 2,4,6-trimethylphenyl.)

Catalyst 1 is soluble only in organic solvents; 2 is poorly soluble in organic solvents and water, which makes it difficult to characterize. Complex 2 is, however, sufficiently soluble in refluxing CH2Cl2 to be an effective catalyst. With the cation change from iodide to chloride, catalyst 3 works almost as well as 2; and it is soluble in organic solvents and water.

The catalysts give excellent yields in ring-closing metathesis (RCM), cross-metathesis, and enyne reactions in CH2Cl2. After the RCM reaction of diethyl diallylmalonate, the catalyst is removed by passing the reaction mixture through a short pad of silica gel; and the product is eluted with CH2Cl2. The ruthenium contamination level is <5 ppm, as indicated by inductively coupled plasma mass spectrometry (ICP-MS).

Alternatively, with water-soluble catalyst 3, the CH2Cl2 reaction mixture can be washed with water. After phase separation, the contamination level of the organic phase is below the ICP-MS detection limit. To avoid disposing large amounts of the ruthenium-contaminated liquid, silica gel can be added to the aqueous phase to precipitate ruthenium, leaving only 0.11 ppm residual ruthenium.

The catalysts were used in RCM reactions of biochemical-like substrates and steroid derivatives with good yields. These catalysts are potential alternatives for pharmaceutical processes involving olefin metathesis. (Green Chem. 2012, 14, 3264–3268; José C. Barros)

Glucose polymers form biodegradable nucleic acid carriers. C.-C. Lee at the University of Cincinnati, Y. Liu at Virginia Tech (Blacksburg), and T. Reineke* at the University of Minnesota (Minneapolis) designed degradable plasmid DNA (pDNA) carrier systems that contain glucose-based polyesters. The authors condensation-polymerized a diacrylate glucose monomer with benzyl-protected oligoamine monomers to yield a protected form of the degradable polyesters. The oligoamines contained three or four ethyleneimine units per monomer molecule.

The poly(ester amine)s had polydispersities of ≈1.7–1.9 and Mn values of ≈14–15 kDa. After the pH-sensitive polyesters were deprotected, they were complexed with pDNA in water. The resulting polyplexes had ≈60 nm diam and exhibited high zeta potentials.

The authors showed that the carriers degrade by measuring the degree of polyplex formation. Degradation is faster in a pH 7.4 buffer than at pH 5.0. Release of acidic degradation products reduces solution pH.

The polyester carrier prevents pDNA degradation upon exposure to nuclease and promotes cellular uptake. But the carrier (particularly the one with higher amine content) hinders gene expression. (ACS Macro Letters 2012, 1, 1388–1392; LaShanda Korley)

Make membrane-permeable imaging nanoparticles by mixing fluorogens with surfactants. Nanoparticles of conventional organic dyes often have poor membrane permeability and weak light emission because of their hydrophobicity and aggregation-induced quenching effects. Although incorporating ionic groups into organic dyes can improve their miscibility with biological media, the dyes still aggregate easily because of their hydrophobic conjugated cores. The electric charges of the ionized dyes may affect intracellular physiology and even cause cell lysis.

To solve these problems, L. Tao, Y. Wei, and coauthors at Tsinghua University and the Chinese Academy of Sciences (both in Beijing) prepared nanoparticles with ≈400–600 nm diam by mixing a fluorogen that has aggregation-induced emission (AIE) properties with a commercial nonionic surfactant.

The AIE characteristic of the fluorogen made the nanoparticles highly emissive, and the surfactant’s cytophilicity made them membrane-permeable. The AIE-active nanoparticles are excellent cellular imaging reagents. (Nanoscale 2013, 5, 147–150; Ben Zhong Tang)


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