Noteworthy Chemistry

January 19, 2015

Suppress drug efflux with a fragment-based strategy. Cellular efflux pumps expel unwanted substances, such as microbial drugs. Consequently, the pumps can cause bacterial drug resistance and interfere with the effectiveness of therapeutic small molecules.

J. K. Sello and colleagues at Brown University (Providence, RI) report a method for developing compounds that interfere with drug efflux. Because efflux requires the pump to recognize and bind all or part of a molecule for export, a fragment of that molecule might be used for competitive interference.

The authors tested their idea by looking for small molecules to inhibit the efflux of cyclic acyldepsipeptides (ADEPs), a group of antibacterial drug leads. ADEPs work well against many Gram-positive bacterial pathogens, but as a result of efflux pumping, they are ineffective against Mycobacterium tuberculosis, which causes tuberculosis.

Compounds that potentiate ADEP activity

The authors synthesized molecules that are substructures of ADEP. Of the ADEP fragments, only the sidechain moiety N-(E)-2-heptenoyldifluorophenylalanine methyl ester (compound 1 in the figure) potentiated ADEP activity in a dose-dependent manner. Positional scanning analysis of 1 showed that derivatives with a primary or secondary amide are superior ADEP potentiators. Compound was the most effective. 

The authors tested 2 in Streptomyces coelicolor strains that express a transporter linked to ADEP resistance. They found that 2 is a strong potentiator at a 1:4.5 mol ratio with ADEP. This indicates that the transporter acts preferentially on the fragment that competitively interferes with ADEP efflux. The authors tested 2against M. tuberculosis and found that it potentiates at a 1:5 2/ADEP mol ratio. 

The researchers believe that this strategy for suppressing compound efflux can be extended to any small molecules that are acted upon by efflux pumps without knowledge of the pumps’ identity, structure, or mechanism. In addition, the technique might provide insights into how efflux pumps recognize compounds, information that could be used to design efflux-resistant drugs. (ACS Infect. Dis. DOI: 10.1021/id500009f; Abigail Druck Shudofsky)

[ACS Infections Diseases is ACS’s newest journal. It was launched in January 2015.—Ed.]

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Tailor cellular foams for oil absorption. Efficient, selective material systems are important for environmental remediation operations such as cleaning up oil spills. Open-cell foams tailored and manufactured for superhydrophobicity and oleophilicity should have distinct advantages.

C. B. Park and co-workers at the University of Toronto used a high-throughput tandem extrusion process coupled with carbon dioxide injection to make open-cell foams with high aspect ratios. The foams consist of mesoporous poly(tetrafluoroethylene) (PTFE) fibrils in a polypropylene (PP) matrix. The interconnected cellular structure has a high void fraction (0.92), cell diameters that range from 50 to 500 μm, and significant thermal stability.

The oleophilicity of the PP-PTFE foams is demonstrated by their rapid (≈0.7 s) absorption of gasoline droplets. The foams’ low densities and superhydrophobic properties allow the foam structure to float after oil uptake.

The authors report oil uptakes from 5 to 24 g/g of foam. Uptake depends on the viscosity of the tested petroleum product. The oil-laden foams can be regenerated by vacuum extraction; oil uptake deviated minimally for >10 absorption cycles.

To increase the mechanical robustness of the foam, the authors replaced the PP matrix with poly(propylene-co-ethylene), which reduced permanent strain during compression cycling measurements. (ACS Appl. Mater. Interfaces DOI: 10.1021/am506006v; LaShanda Korley)

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Water sets off luminescent carbon nanodots. Carbon nanodots (CDs) are carbon-based nanoparticles that usually exhibit strong, stable photoluminescence. Because of their high water solubility, low cost, and chemical inertness, CDs are promising materials for applications ranging from optoelectronics to bioimaging.

CDs have received much attention as functional materials, but until now, little research focused on developing CDs into complex assemblies with desirable properties. S. Qu, D. Shen, and coauthors at the Chinese Academy of Sciences (Changchun Jilin), the University of Chinese Academy of Sciences (Beijing), and the University of Amsterdam designed and synthesized so-called supra-CDs with switchable luminescence derived from chemical functionalization of the CDs.

The authors prepared CDs rich in hydrophilic amide groups from citric acid and urea. They then coupled them with 1-bromododecane to obtain amphipathic CDs. Through amphiphilic interactions, these CDs readily assemble in toluene into supra-CDs (assemblies of CDs much like surfactant micelles). This aggregation quenches the CDs’ luminescence.

When supra-CDs are deposited on paper, their fluorescence quantum yield can be enhanced from almost none to as much as 40.6% upon contact with water, which induces the disintegration of the aggregates. This property allows the supra-CDs to be used for water-jet printing and sweat-pore patterning from fingerprints.

Water-enhanced luminescence of the super-CDs also makes them suitable for use in humidity sensors and water-content indicators. The authors believe that given the low cost and ease of manufacture, supra-CDs responsive to other specific stimuli or stimulus combinations may be developed for additional applications. (Adv. Mater. DOI: 10.1002/adma.201403635; Xin Su)

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Use electrochemistry to identify API oxidation products. Stability studies are important components of the approval process for new active pharmaceutical ingredients (APIs). One of the most common degradation pathways for APIs is oxidation, which in lab studies is mimicked by using oxidizing agents such as peroxides or iron(III) chloride. But these reagents are often nonselective and produce mixtures of oxidized products that must be characterized.

Recently, researchers showed that electrochemistry, in conjunction with liquid chromatography (LC) and/or mass spectrometry (MS), is useful in API metabolism studies. Now, S. Torres and co-workers at Pfizer Worldwide R&D (Sandwich, UK; and Groton, CT) report that electrochemistry can imitate oxidative drug metabolism by cytochrome P450 as an oxidative stress condition for preparing milligram quantities of degradation products.

The authors chose fesoterodine (1 in the figure), a drug for treating overactive bladder syndrome, as their model compound. They subjected it to a constant 950 mV potential to obtain two oxidation products, a secondary amine (2) and an aldehyde (3). Voltammetry studies indicated that oxidation occurs between 600 and 1000 mV.

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Electrochemically produced oxidation products from fesoterodine

The authors then performed a design-of-experiments study to screen several conditions such as pH, electrolyte and substrate concentration, and percentage of organic solvent in the sample. The results showed that higher pH values and acetonitrile solvent concentrations favored the formation of 2. The factors favoring formation of 1 were unclear because the data indicated that 1 participates in a second oxidation step to form 2.

This method is a fast, efficient, environmentally friendly alternative for determining API oxidation products. (Org. Process Res. Dev. DOI: 10.1021/op500312e; José C. Barros)

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This breathalyzer senses cancer. Effective cancer treatment relies on early detection and accurate assessment of treatment efficacy. One promising area of research is the identification of volatile organic compounds (VOCs) emitted by cancer cells. An ideal detector for these VOCs would detect low concentrations, respond rapidly to small changes in concentration, and provide a consistent output in response to a specific exposure.

H. Haick and coauthors at Technion—Israel Institute of Technology (Haifa); Max Planck Institute for the Science of Light (Erlangen, Germany); and the University of Latvia, Riga East University Hospital, and Digestive Diseases Center GASTRO (all in Riga, Latvia) developed an ultrasensitive VOC sensor and evaluated its effectiveness in a small pilot clinical study on exhaled breath samples. In a blind analysis, this sensor accurately discriminated between volatile compounds emitted by gastric cancer cells and control compounds, irrespective of such factors as tobacco consumption, Helicobacter pylori infection, and gender.

The sensor consists of an individual surface-modified silicon nanowire field-effect transistor (SiNW FET) with lock-and-key features that responds differently to various VOCs at the low-ppb level. The sensor also uses pattern-recognition methods for analyzing its response to complex mixtures. The authors tested various SiNW FET surface coatings for sensitivities to three compounds associated with gastric cancer cells and two compounds that exist in exhaled breath but do not correlate with the presence of cancer cells.

The sensors were evaluated with real breath samples from 30 cancer patients and 77 "healthy" volunteers, some of whom had dyspeptic symptoms but not cancer. Discriminant factor analysis was used to find the best possible separation between the cancer patients and the healthy volunteers.

Of the coatings tested, trichloro(phenethyl)silane produced the greatest sensitivity (5 ppb) toward the cancer-related VOCs and the greatest response difference between these compounds and the two non–cancer-related compounds. The training set for this coating showed 87% sensitivity, 81% specificity, and 83% accuracy. Plotting the blind samples onto this model achieved 71% sensitivity, 89% specificity, and 85% accuracy. The sensor distinguished little between smokers and nonsmokers and between patients with and without H. pylori infections.

This sensor had a sensitivity of 92% and a specificity of 67% for discriminating between advanced and early-stage gastric cancer. The authors suggest that the low specificity might be related to the small number of early-stage gastric cancer cases evaluated. (Nano Lett. DOI: 10.1021/nl504482t; Nancy McGuire)

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Minimize safety problems from reactions in dimethyl sulfoxide solvent. Z. Wang and colleagues at AbbVie (North Chicago, IL) describe thermal hazard analysis studies on two reactions that use dimethyl sulfoxide (DMSO) as the solvent: a Pfitzner–Moffatt oxidation and a Corey–Chaykovsky cyclopropanation. Completely eliminating DMSO from both reactions is unfeasible because DMSO is used as a reagent in the oxidation reaction and is a byproduct of the cyclopropanation.

In both cases, other reactants lower the decomposition onset temperature of DMSO from its boiling point (189 ºC) to 140–150 ºC, a temperature range that can be reached if the heating system malfunctions. The safety of the Pfitzner–Moffatt oxidation can be significantly improved by using N,N-dimethylacetamide as solvent, but 8 equiv DMSO is still required for good conversion. Using dimethylformamide as the solvent for the Corey–Chaykovsky cyclopropanation provides a process without safety problems from ylide formation or the cyclopropanation process. (Org. Process Res. Dev. DOI: 10.1021/op500260n; Will Watson)

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