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Super-fast crystals

Identification of all solid forms of a pharmaceutical is important for drug delivery, due to the potential variability in the physical and chemical properties between amorphous and crystalline forms. The amorphous form of a compound is typically more soluble, but less stable than its crystalline counterpart. Not only that but different polymorphs of the crystalline compound can also have significantly different properties.  To accurately characterise drug action, these polymorphs need to be identified.

Using small-scale crystallisation and in-situ Raman spectroscopic analysis of the antihypertensive drug, nifedipine, Franziska Emmerling and colleagues discovered an extraordinarily fast transition from the glassy amorphous state to the metastable β polymorph in less than a minute. The β polymorph is stable for less than ten minutes before transforming again, to the thermodynamically stable α polymorph.

The speed at which the transformations take place implies that classical diffusion is not responsible for the different polymorphs but could instead be the result of small intramolecular changes arising from a pre-ordered physical arrangement of the molecules.

In an industrial world where screening for solid drug forms is always leaning towards scale-reduction and time-reduction, three physical forms on a glass slide in less than twenty minutes is pretty impressive!

To find out more, download the ChemComm article.

Also of interest…  Read Andrew Bond, U. Ramamurty, and Gautam Desiraju’s Chemical Science article on “Interaction anisotropy and shear instability of aspirin polymorphs established by  nanoidentation“.

Posted on behalf of Scott McKellar, web science writer for ChemComm.

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Hybrid biofuel cell

Scientists from Israel have designed a biofuel cell that combines the advantages of both enzymatic and microbial fuel cells.

Biofuel cells use redox enzymes to convert chemical energy into electricity. These cells can be divided into two categories: enzymatic fuel cells which require the enzymes to be purified and microbial fuel cells which make use of an entire microorganism. There are pros and cons to both strategies – enzymatic fuel cells tend to have increased power output whilst microbial fuel cells enable full oxidation of a wider range of fuels.

Yet now, Lital Alfonta and co-workers demonstrate that by designing a hybrid cell, one can have the best of both worlds. The team have modified yeast to display redox enzymes on their surface and then introduced this into both the anode and cathode compartments. This approach removes the need to purify the enzymes and enables regeneration of both fuel compartments.

To find out more about Alfonta’s biofuel cell device, read the ChemComm article today.

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Nitron, the new N-heterocyclic carbene

N-heterocyclic carbenes (NHCs) are extremely useful reagents in synthesis and catalysis, but unfortunately they are expensive with 1 gram costing several hundred US dollars.

However, as Ulrich Siemeling and his colleagues report in their latest ChemComm, it seems that a much cheaper alternative is on the horizon… 

The team of scientists based at the University of Kassel have discovered that Nitron, a low cost analytical reagent, exhibits surprising NHC reactivity, more akin to that of its tautomeric form than its conventional Lewis structure. By reacting Nitron with typical carbene trapping reagents such as elemental sulphur, CS2, and rhodium complexes, they have proven that it is indeed Nitron’s tautomer that it responsible for its NHC-like reactivity in solution, despite being present at concentrations undetectable by NMR spectroscopy.

At a fraction of the price and already commercially available, Nitron may soon become a very popular choice in NHC reactions.

To read more about how Siemeling and co-workers established the cause for Nitron’s unusual reactivity, download the ChemComm article.

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Once, twice, three times a potential life saver – electrochemical immunoassay of cancer biomarkers

Early detection and diagnosis of cancer is essential to give sufferers an increased chance of overcoming the disease. The symptoms of liver cancer, in particular, are fairly innocuous – tumours are difficult to detect by physical examination and therefore the disease is not usually discovered until the later stages of development.

Dong Wang and co-workers have developed an electrochemical immunoassay which has the potential to improve the early detection rates of liver cancer by simultaneous detection of not one, not two, but three tumour markers. This simultaneous multianalyte immunoassay (SMIA) has a number of advantages over single-analyte immunoassay methods such as reduced overall cost per assay; improved efficiency; the potential to quantitatively measure the concentrations of proteins detected; as well as having a panel of biomarkers to confirm the diagnosis, lowering the likelihood of false-positive or false-negative results.

The team selected three electrochemical redox species with distinct voltammetric peaks to label three different antibodies as signal tags. These were then loaded onto carbon nanotubes coated with gold nanoparticles to improve the signal response.

Binding of the redox species labelled nanotube-antibody conjugates to the cancer biomarkers enables their electrochemical detection

By deciphering the voltammetric read-out, the team were able to establish successful binding events between the probes and the protein biomarkers, allowing simultaneous identification of the three analytes. Wang and his team then increased the sophistication of the immunoassay further by proving quantitative detection.

Dong Wang and co-workers appeared to have produced a robust SMIA with low detection limits that has the potential to save many lives. This efficient, gold nanoparticle-based technology could also be applied to other types of cancer or diseases – an immunoassay with a Midas touch.

To find out more, download the ChemComm article.

Posted on behalf of Sarah Brown, ChemComm web science writer.

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Overcoming obstacles in labelling RNA

If you can’t beat them, join them… or rather incorporate, and then join them together. This is the approach adopted by Srivatsan and colleagues for conjugating labels to RNA, which they achieve by incorporating azide functionality into RNA nucleotides.

DNA oligonucleotides are routinely labelled by incorporating modified nucleosides into the desired DNA sequence and introducing the label post-synthesis; however, these standard methods offer low yields of the desired conjugate. Furthermore, modification of RNA is more challenging than DNA modification due to its inherent instability.

Copper catalysed alkyne–azide cycloadditions (CuAAC) and Staudinger ligations are the conjugation reactions du jour due to their high chemoselectivity and reported high yield. So, with this in mind, were Srivatsan and his team able to incorporate the required moieties into RNA oligonucleotides?

Yes! Using some extremely nice chemistry, they synthesised an azide-modified nucleotide and incorporated it into an oligoribonucleotide using in vivo transcription reactions in the presence of a series of promoter-template oligonucleotides. After rigorous testing and analysis of their modified nucleic acid sequence, click reactions were performed to yield biotinylated and fluorescent-labelled click products. They also showed that amine functionality can be introduced through Staudinger ligation.

Although azides are not usually found in nature, they are becoming more useful and versatile in the design of diagnostic and therapeutic biological probes as has been very elegantly demonstrated here.

Read more in Srivatsan’s ChemComm article

Also of interest: Synthetic DNA synthesises RNA by transcription: ‘click’ here for more

Posted on behalf of Sarah Brown, web science writer for ChemComm.

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Green hydrogenation of cyclic di-esters to diols

Hydrogenation of esters under mild conditions is difficult at best, however David Milstein and his team push the boundaries by hydrogenating biomass products, glycolide and lactide, to afford the corresponding 1,2-diols. Their synthesis, which utilises ruthenium pincer complex catalysts, offers an atom-economical, green alternative to existing methods for producing 1,2-diols, which currently rely on petroleum-derived ethylene and propylene feedstocks.

The team say that the cyclic di-esters can be selectively and efficiently hydrogenated under very mild conditions, whilst producing no waste, and even discovered that optically pure diols could be produced from chiral lactide.

Download the ChemComm article today to find out how Milstein and his team did this.

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Aromaticity web theme issue – welcoming submissions

We are delighted to announce a high-profile web themed issue on Aromaticity.

Guest editors: Nazario Martín (University Complutense of Madrid), Michael Hayley (University of Oregon) and Rik Tykwinski (University of Erlangen-Nuremberg)

This themed issue will consist of a series of invited Communications and Feature Articles covering work on all aspects of chemistry related with aromaticity – from new fundamental knowledge about aromaticity and theoretically interesting new arene structures to novel applications of aromatics and heteroaromatics which take advantage of their unique optical and electronic attributes.

The level of quality of this issue will be extremely high, and all manuscripts will undergo strict peer review. You are therefore encouraged to report work that you consider to be very important and conceptually significant. Please note that inclusion in the issue is subject to the discretion of the guest editors.

Publication of the peer-reviewed articles will occur without delay to ensure the timely dissemination of the work. The articles will then be assembled on the ChemComm website as a web-based thematic issue.

Submit your work before 31st May 2012. Please add “aromaticity” in the comments to the editor section.

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Further insight into aromatic borylation chemistry

Thorough characterisation of arene–borane Lewis acid contacts is essential for understanding the mechanistic pathway for aromatic borylation chemistry and by extension, electrophilic aromatic substitution. However, until now, structural determination of such arene–borane compounds has been somewhat ambiguous.

Simon Aldridge and his team have set out to fill this knowledge gap by reacting a sterically encumbered pyridine donor with BBr3 to yield a cationic tri-coordinate borane–arene complex. Employing crystallography and computational studies, the team found that a weak electrostatic interaction is responsible for the short contacts between the positively charged boron centre and the arene π system.

Read the ChemComm article to find out more…

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Synthetic DNA synthesises RNA by transcription: ‘click’ here for more

What’s better than a short synthetic DNA sequence? That’s right: a long synthetic DNA sequence, able to take part in biological processes.

DNA and RNA are routinely synthesised using solid phase synthesis, connecting the bases through phosphodiester linkages.  This method, however, imposes limitations on the length of the strand produced. Current methods employ enzymes to achieve larger oligonucleotides, which have disadvantages such as poor quality and stability and can be laborious.

Tom Brown and Afaf El-Sagheer at the University of Southampton, UK, have now demonstrated that these limitations can be overcome by the flick of a ‘click’ – they chemically ligated oligonucleotides functionalised with chemoselective azide and alkyne moieties using click chemistry to produce long nucleic acid sequences. After personally struggling to conjugate biological moieties using click chemistry for my Ph.D., I can assure you this is no mean feat!

Previous work by the group has shown that oligonucleotides with triazole-modified backbones do not inhibit replication and so they were interested to see if the same would be true for transcription – a fundamentally different process. The primary concern was how modification of the phosphodiester backbone would affect the template strand’s ability to participate in the transcription process.

By synthesising two triazole-modified DNA template strands, one with the triazole unit in the coding sequence and the other with the modification in the T7 RNA promoter region, El-Sagheer and Brown were able to evaluate the impact of changing the template strand backbone in comparison with the equivalent non-modified templates. Both modified strands successfully took part in transcription to produce RNA in good yield.  The result: fully-synthetic, biologically-active DNA templates successfully synthesising RNA. This is not only an elegant demonstration of the abilities of click chemistry but could also be fundamental in changing approaches to the synthesis of biological constructs.

To read more about Brown’s research, download the ChemComm article today.

Posted on behalf of Sarah Brown, web science writer for ChemComm.

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Fullerene ‘hide and seek’ in lipid membranes

Japanese researchers have experimentally proven that fullerenes reside in the hydrophobic core of liposome membranes.

Liposomes are vesicular structures made up of a phospholipid bilayer. Due to their ability to encapsulate a range of different substances and target numerous cell types, they have great potential as drug delivery agents. Recently, liposomes have been modified with fullerene for a number of uses such as DNA photocleavage, anti-bacterial agents, and photodynamic therapy. Although theoretical simulations have been performed to characterise these fullerene–liposomes, up until now there has been no experimental proof of where the fullerene units end up in the lipid membranes.

Using differential scanning calorimetry and 13C NMR spectroscopy, Atsushi Ikeda and colleagues have determined that the fullerenes self-aggregate in the core of the bilayer, separating themselves from the alkyl chains. The fullerene units are expected to be located in a similar fashion in a cell membrane, say the team. This new insight means efforts can commence on bringing the fullerenes up to the surface of the lipid which may help improve the photoactivity of the fullerenes whilst reducing any deleterious effects they may have.

Download Ikeda’s ChemComm article to find out more…

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