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Noteworthy Chemistry

February 23, 2015


Use biocompatible fluorescent nanoparticles to trace live cells. Developing fluorescent bioimaging systems for long-term cellular tracing has great implications for medicine, especially for tumor metastasis research. Quantum dots have been used as cell trackers, but their high cytotoxicity limits the scope of their in vivo applications. Scientists also have attempted to use organic nanoparticles (NPs), but the NPs often emit weak light in aqueous media because of aggregation-induced quenching.

Y. Zhao, L. Gan, C. Zhang, and co-workers at Huazhong University of Science and Technology and the National Engineering Research Center for Nanomedicine (both in Wuhan, China) developed biocompatible, emissive polymer NPs for long-term cell tracing applications.

The researchers used N-isopropylacrylamide (1 in the figure) as the monomer, a tetraphenylethylene (TPE) derivative with two terminal bromine atoms (2) as the radical initiator, and atom-transfer radical polymerization (ATRP) to synthesize TPE-containing poly(N-isopropylacrylamide) (PNIPAM) (3). The macromolecules self-assemble into NPs (4) in water. 

Preparation of fluorescent TPE-PNIPAM nanoparticles

Individual polymer molecules are nonemissive, but their nanoaggregates fluoresce efficiently, exhibiting the aggregation-induced emission effect. The particle size and fluorescence intensity of the nanoaggregates can be tuned by changing the temperature. The NPs can be easily internalized by HeLa cancer cells with no cytotoxicity. They make it possible to trace the stained cells for as long as 15 days or seven incubation cycles. (ACS Appl Mater. Interfaces DOI: 10.1021/am509161y; Ben Zhong Tang)

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Transcription factor phospho-regulation drives pathogenesis. The fungus Candida albicans lives on the skin and on mucosal surfaces of the gastrointestinal and vaginal tracts. Although generally harmless, this opportunistic pathogen causes infections that range from superficial to life-threatening. C. albicans grows as ovoid yeast or filamentous hyphal cells; the latter form can escape the host immune response and invade internal organs.

When C. albicans switches from the yeast to the hyphal form, transcriptional changes cause it to express pathogenic proteins. Y. Wang, P. E. Sudbery, and coauthors at the University of Sheffield (UK), the Agency for Science, Technology and Research (Singapore), the University of Oxford (UK), King’s College London, and the National University of Singapore investigated the role of protein phospho-regulation in C. albicans morphogenesis and pathogenesis. They looked for proteins that are specifically phosphorylated in the hyphal state.

The authors found that the phosphorylation profile of the fork-head family transcription factor Fkh2 changes drastically within 5 min of hyphal induction. During yeast growth, Fkh2 typically has a housekeeping function and is regulated in a cell-cycle–dependent manner. But during hyphal growth, it is phospho-regulated in a cell-cycle–independent manner.

Microarray analysis showed that Fkh2 phospho-regulation is specifically needed to activate and regulate a subset of genes that, when expressed, promote invasive growth and host pathogenesis. The authors mapped the phosphorylated residues to six consensus sites for the kinase Cdc28. They also found strong evidence that Fkh2 is targeted by the kinase Cbk1-Mob2.

The phosphorylation is necessary for C. albicans to transition to and develop in the hyphal form. This study uncovered a new way for protein phosphorylation to regulate virulence and determine pathogenesis. (PLoS Pathogens DOI: 10.1371/journal.ppat.1004630; Abigail Druck Shudofsky)

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“Decorate” carbon nanorings. Cycloparaphenylenes (CPPs) are macrocyclic compounds that consist of benzene rings connected at their para positions. They are the shortest segments of “armchair” carbon nanotubes. CPPs are strained cyclic molecules with radially conjugated π-orbitals that can interact with metal cations. Their π-systems are similar to those of fullerenes.

By taking advantage of the reactivity of the radial π-conjugation in CPPs, N. Kubota, Y Segawa, and K Itami* at Nagoya University (Japan) prepared a series of η6 transition-metal complexes of [9]- and [12]CPPs. The metal complexes can be used as starting materials for conveniently monofunctionalizing CPPs.

The authors treated [9]CPP (1 in the figure) with 1 equiv chromium hexacarbonyl [Cr(CO)6,] to produce η6-[9]CPP-Cr(CO)3 (2) in 35% yield after 10 h at 160 ºC. In this complex, one of the C6H4 benzene rings is coordinated to chromium. [9]CPP-Mo(CO)3 and [9]CPP-W(CO)3 were similarly prepared, along with complexes that contain [12]CPP as the ligand. The structures and photophysical properties of these complexes were studied in detail by using various spectroscopic techniques, X-ray crystallography, and time-dependent density functional theory calculations.

Preparation of CPP–chromium complex

η6-Coordination to metals in CPPs changes the reactivity of the arene ligands and allows selective aromatic C−H activation. For example, monodeprotonating [9]- and [12]CPP metal complexes with n-butyllithium allows them to couple to a range of electrophiles, including trimethylsilyl, carbomethoxy, and boron pinacolate groups.

This study provides insights into the reactivity of the unique π-systems in CPPs and adds another example to the exotic collection of radial π-conjugated metal complexes. More importantly, selective C−H activation for CPPs with these complexes provides access to a variety of precisely functionalized CPP nanorings. (J. Am. Chem. Soc. DOI: 10.1021/ja512271p; Xin Su)

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Change to “greener” solvents in peptide couplings. Peptide coupling is an important reaction in organic and medicinal chemistry. N,N-Dimethylformamide (DMF) is the most widely used solvent for this reaction, but it is undesirable because of its environmental risks.

A. El-Faham at Alexandria University (Egypt), F. Albericio at the Institute for Research in Biomedicine–Barcelona, and coauthors on four continents replaced DMF with the more environmentally acceptable solvents tetrahydrofuran (THF) and acetonitrile (ACN) in peptide-coupling reactions and compared yields and product racemization. They began the study with solution-phase syntheses of a dipeptide and a tripeptide that were mediated by N,N’-diisopropylcarbodiimide in the presence of additives such as HOBt, HOAt, OxymaPure, and Oxyma-B. The results indicated that THF and ACN performed better than DMF.

Next, the researchers compared the solvents in the stepwise preparation of a pentapeptide and in the solid-phase production of a decapeptide from two pentapeptides. In all cases, THF and ACN had higher coupling efficiencies than DMF, and the products had higher yields and purities. These “greener” solvents should be excellent replacements for DMF in peptide coupling. (Org. Biomol. Chem. DOI: 10.1039/C4OB02046D; José C. Barros).

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Cicada wings provide a clue to light harvesting. Cicada wings exhibit <1% light reflectance over the visible spectrum, which makes them very efficient at absorbing light. Design development for effective, economical light-harvesting structures is a new field; the cicada's light-harvesting ability would be useful for controlling the optical performance of these optoelectronic devices.

Cicada wing surfaces are covered in nanotip structures that resemble arrays of pointed spikes. The figure shows a photographic image (left) and a top-view scanning electron microscope image (right) of a cicada wing.

Photograph and scanning electron micrograph of a cicada wing

K.-H. Chen, S Chattopadhyay, and colleagues at National Yang Ming University, National Taipei University of Technology, National Taiwan University, and Academia Sinica (all in Taipei, Taiwan [Province of China]) created surface structures that imitate these spiky arrays by using low–refractive index (e.g., silica and indium tin oxide) and high-index (e.g., silicon and germanium) photovoltaic materials. The biomimetic structures had short spikes on the surface, whereas other structures had taller, sharper spikes. The authors varied the spacings, lengths, and refractive indices of the spikes to see which configurations came closest to the target of 1% reflectance or less.

The authors screened potential materials and geometries with the use of calculations and theoretical modeling. For silica, reflectance decreases almost to 1% as the ratio of the spike spacing to the incident light wavelength increases to almost 0.1. Greater spacing would be required to reduce the reflectance to the same degree for a material with a greater refractive index. Increasing the ratio of the spike lengths to their spacing also decreases reflectance.

The authors studied variations in the reflectance of laboratory samples with the angle of incidence and degree of polarization of the incident light. They found that, in contrast to a polished silicon surface, a silicon nanotip spike surface is remarkably insensitive to both of these factors at incident angles <70°; and it becomes even less sensitive as the length of the spikes increases. (ACS Nano DOI: 10.1021/nn506401h; Nancy McGuire)

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Don’t let diborane escape from a borohydride reduction. T. Naka and co-workers at Mitsubishi Tanabe Pharma Corp. (Osaka) describe mechanistic and safety studies conducted during the development of a scalable lactam reduction with sodium borohydride (NaBH4) and trifluoroacetic acid (CF3CO2H or TFA). 11B NMR studies indicated that there are two types of reducing species present in the reaction: boranes and sodium trifluoroacetoxyborohydrides.

Safety studies showed that the reaction is exothermic; about half of the generated heat comes from the reaction between NaBH4 and TFA. Analysis of the gas evolved during the reaction showed the presence of diborane (B2H6), which must be reduced to <10 ppb before the gas is released to the atmosphere. Slow addition of TFA and two 15% sodium hydroxide scrubbers were required to reach the required level. (Org. Process Res. Dev. DOI: 10.1021/op500284e; Will Watson

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HOBt = 1-hydroxybenzotriazole; HOAt = 1-hydroxy-7-azabenzotriazole; OxymaPure = ethyl 2-cyano-2-(hydroxyimino)acetate; Oxyma B = (5-(hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione