Noteworthy Chemistry

July 7, 2014

Lipophilic vancomycin analogues overcome resistant bacteria. Glycopeptide antibiotics such as vancomycin are useful for treating infections in intensive care units, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The emergence of vancomycin-resistant staphylococcus and enterococcus bacteria, however, is a public health concern that requires the development of new antibiotics.

J. Haldar and co-workers at Jawaharlal Nehru Center for Advanced Scientific Research (Bengaluru, India) prepared lipophilic cationic vancomycin derivatives (1) and tested them against drug-resistant bacteria. They prepared the compounds by using standard peptide-coupling reactions between vancomycin and lipophilic quaternary ammonium cations with various side chains (see figure).

Synthesis of lipophilic vancomycin derivatives

Methicillin-sensitive S. aureus (MSSA)
Methicillin-resistant S. aureus (MRSA)
Vancomycin-intermediate-resistant S. aureus (VISA)
Vancomycin-sensitive E. faecium (VSE)
Vancomycin-resistant E. faecium (VRE)

The authors tested the derivatives in vitro against the staphylococcus and enterococcus bacteria listed in the insert. The tested compounds had activities similar to vancomycin against MSSA, MRSA, and VSE. Against VISA and VRE, however, the cationic unit contributed significantly to antibacterial activity, which increased with the length of the side chain. The authors attribute the increased activity to disruption of the bacterial membrane by the lipophilic chain.

Whole-blood assays indicated that the compounds maintain their bacterial activity in vivo and are nontoxic. The most active compound (1, R = n-octyl) showed excellent activity in a MRSA-infected mouse model. These compounds should be promising candidates against drug-resistant bacteria. (J. Med. Chem. DOI: 10.1021/jm500270w; José C. Barros)

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A simple ionizer generates molecular ions with no fragments. Mass spectrometry is a widely used analytical technique that provides information about the mass of molecules and molecular fragments. A typical mass spectrometer relies on its ionizer to generate ions to feed to the detector and mass analyzer. Numerous ionization techniques exist, but new methods for ionizing substances under ambient conditions without complex instrumentation are highly desirable.

T. Pradeep and coauthors at the Indian Institute of Technology Madras and Purdue University (West Lafayette, IN) developed a simple yet efficient molecular ionization technique that uses carbon nanotube (CNT)–functionalized paper. Their ionizer consists of triangles of CNT-coated filter paper that are wetted with methanol–water and connected to a 3-V battery.

The authors first tested the ionizer’s ability to ionize triphenylphosphine (PPh3). It produced a mass spectrum with an m/z peak at 263, indicative of protonated PPh3. Increasing the applied voltage to 3 kV led to higher signal intensity for the molecular ion, but no fragmentation or oxidation products that would appear under conventional ionization conditions were observed.

The authors’ method can be applied to a variety of analytes and physical states. Some examples are pesticides on fruit surfaces and active ingredients in medicine tablets. The straightforward process involves rubbing the CNT-coated paper on sample surfaces without any pre- or post-treatment.

The authors believe that the system operates by a nanotube spray mechanism, in which a high electric field can be generated through CNT protrusions even at low applied voltages. The electric field induces a field emission of solvated species as charged microdroplets. (Angew. Chem., Int. Ed. DOI: 10.1002/anie.201311053; Xin Su)

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Why don’t octopus tentacles adhere to each other? Picture an octopus with its suckered tentacles flailing about. Those suckers reflexively stick to almost anything. Have you ever wondered why one tentacle does not stick to, grab, or interfere with another tentacle?

B. Hochner and colleagues at the Hebrew University of Jerusalem, Ruppin Academic Center (Michmoret, Israel), and the City University of New York (Brooklyn) discovered that the skin on an octopus arm releases specific chemical signals to restrict the sucker attachment reflex and prevent suckers on one tentacle from grabbing another tentacle.

Octopus arms are sensory organs that are covered with ≈40 million chemical and tactile receptors that are present all over the tentacles. A large concentration of the receptors are on the rims of the suckers. The authors believe that chemicals released by the arm skin locally inhibit the attachment reflex of each individual sucker. The released molecules are likely hydrophobic because they can be easily extracted and dissolved by hexane.

And—if you’ve ever wondered why octopuses don’t get tangled up in each other’s arms—they can even differentiate between their own tentacles and those of other octopuses. This observation suggests complex self-recognition mechanisms beyond suckers and skin. (Curr. Biol. DOI: 10.1016/j.cub.2014.04.024; Abigail Druck Shudofsky)

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A dansyl fluorogen detects aluminum ion with high specificity. Intramolecular charge transfer (ICT) occurs in molecules that contain donor (D) and acceptor (A) units. Light emission from ICT fluorogens is often boosted and blue-shifted when the polarity of its environment decreases. From a dansyl-substituted ICT system with a D–A structure (1 in the figure), Y.-B. Ruan, A. Depauw, and I. Leray* at the d’Alembert Institute (Cachan, France) developed a fluorescent sensor for Al3+ ion that has great sensing specificity and tolerates interference well. The dansyl group is 5-(dimethylamino)naphthalene-1-sulfonyl.

Fluorogen 1 emits weak yellow light in a lutidine buffer at pH 6. Its fluorescence is enhanced and its emission color shifts to green when it is added into an Al3+-containing buffer. Its response to Al3+ is very fast; and its detection limit is 1.8 µM, which meets the requirement of the World Health Organization for drinking water ([Al3+]  £ 7.41 μM). Sensing performance is not affected by many competing ionic species, illustrating great resistance to interference.

At pH <4, Al3+ exists in solution as [Al(H2O)6] 3+; but at pH 6, it precipitates as Al(OH)3. The negatively charged molecules of 1 are adsorbed onto positively charged particles of Al(OH)3 via electrostatic interactions. The reduction in the environmental polarity of the ICT fluorogen from the aqueous medium to the nanoaggregate surface leads to enhanced emission with a blue-shifted color. (Org. Biomol. Chem. DOI: 10.1039/C4OB00187G; Ben Zhong Tang)

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Prevent a byproduct from forming an impurity. M. L. Maddess and co-workers at Merck (Rahway, NJ, and Hoddesdon, UK) developed a route for making kilogram quantities of an estrogen receptor β-selective agonist. In the penultimate step of the synthesis, a trifluoromethyl (CF3) group is introduced by treating a 2-iodocyclohexenone with methyl fluorosulfonyldifluoroacetate (MFDSA, FSO2CF2CO2Me). This step is followed by removing a tert-butyl group that had been used to protect the NH group of a benzotriazole moiety.

The trifluoromethylation reaction is mediated by CuI in dimethylformamide solvent. As the reaction is scaled up, increasing amounts of an impurity that contains a methylated quaternary salt are produced. This occurs because the methyl group in MFDSA is converted to methyl iodide (MeI), which can react with the N-tert-butylbenzotriazole functionality.

Adding a tertiary amine suppresses this side reaction, but the most practical option is to distill the MeI as it forms. In addition, 0.2 equiv of 2,6-lutidine can be added to the reaction mixture to scavenge any HF produced and mitigate reactor etching. (Org. Process Res. Dev. DOI: 10.1021/op5000489; Will Watson)

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Guide drug delivery with near-infrared light. Much effort has been invested in developing controllable, targeted drug delivery systems to enhance therapeutic effects. Drug carriers must be able to release their cargos in response to specific stimuli such as local pH changes or enzymatic triggers when they reach targeted tissues or organs. Progress in nanotechnology has allowed the delicate design of self-assembled hierarchical nanodevices that address this need.

Among many nanoscale functional materials, mesoporous silica nanoparticles (MSNs) have been converted to drug vehicles for “smart” delivery. Y.-W. Yang and colleagues at Jilin University and the Chinese Academy of Sciences (both in Changchun, China) developed self-assembled nanovalves that consist of mesoporous silica–coated gold nanorods that release their cargo when irradiated with near-infrared (NIR) light (see figure).

A dansyl fluorogen detects aluminum ion with high specificity.Intramolecular charge transfer (ICT) occurs in molecules that contain donor (D) and acceptor (A) units. Light emission from ICT fluorogens is often boosted and blue-shifted when the polarity of its environment decreases. From a dansyl-substituted ICT system with a D–A structure (1 in the figure), Y.-B. Ruan, A. Depauw, and I. Leray* at the d’Alembert Institute (Cachan, France) developed a fluorescent sensor for Al3+ ion that has great sensing specificity and tolerates interference well. The dansyl group is 5-(dimethylamino)naphthalene-1-sulfonyl.
Highly specific Al3+ sensor
Drug release from silica–gold nanovalves

The authors used gold nanorod (AuNR) cores coated with mesoporous silica to form the AuNR@MSN nanovalve platform. This combination exhibits red-shifted absorption at ≈ 800 nm in the NIR region. The silica surface was functionalized with quaternary ammonium salt (QAS) stalks, the positive ends of which can be encapsulated by negatively charged sulfonatocalix[4]arene (SC[4]A).

A model drug, rhodamine B (RhB), was loaded into the mesopores of the silica layer before the final capping with SC[4]A. At neutral pH, the nanovalves release the RhB cargo in the presence of ethylenediamine via competitive binding with SC[4]A. Because the association affinity between QAS and SC[4]A drops as the temperature increases, NIR irradiation liberates RhB from the SC[4]A-capped AuNR@MSNs as a result of the photothermal effect. The process has an NIR power–dependent kinetics profile.

More importantly, the authors developed an on–off mode for RhB release that is synchronized to on–off NIR laser irradiation. Because NIR light penetrates tissues well and is benign toward them, it makes an ideal external trigger for targeted drug delivery. This work may lead to highly efficient solutions for noninvasive therapeutic protocols. (Chem. Sci. DOI: 10.1039/C4SC00198B; Xin Su)

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