Take your vitamins: Tocopherol derivatives as new dioxin receptor antagonists

When reactive oxygen species (ROS) hit the body, vitamin E helps to prevent damage to tissues and cells by acting as an antioxidant. The health benefits of vitamin E are numerous, and in fact, studies have found that people with higher levels of vitamin E in their system have a lower risk of heart disease and certain forms of cancer. A team led by Thomas Rosenau from the University of Natural Resources and Life Sciences in Vienna (Austria) now describe their synthesis of a series of modified vitamin E derivatives that show promise as dioxin receptor antagonists in the European Journal of Organic Chemistry.

Chemically, vitamin E is composed of several compounds from the tocopherol and tocotrienol family. The search for novel tocopherol derivatives that possess altered properties, including different lipophilicity or oxidative lability, while still maintaining the physiological benefits of the vitamin is now an important field of study. In this vein, the aryl hydrocarbon receptor (AhR), also called dioxin receptor, is present in most cells and tissue types of the body. AhR is typically inactive, but upon exposure to environmental pollutants, carcinogens, and drugs, for instance, it can form a complex that may be harmful to the body. Several aromatic, fat-soluble derivatives have been identified as key compounds that bind to AhR, and a correlation between their binding and their toxic nature has been documented.

Fluorine-containing aromatic compounds have been shown to be strong AhR antagonists in that they preclude the negative health effects associated with exposure to toxic substances. The Austrian research team reasoned that substitution of the planar aromatic ring of tocopherol compounds with a fluorinated aromatic moiety in combination with their inherent antioxidative and lipophilic properties would produce very suitable ligands for the AhR target. Thus, a small library of substituted tocopherols carrying mono- or difluorinated aromatic substituents was prepared. The authors showed that their compounds were very potent AhR antagonists in vitro, and in fact, their compounds were two to three orders of magnitude more effective than previously known antagonists and comparably as effective as some of the strongest antagonists hitherto known. Thus, patients may someday be able to turn to this new family of vitamin E derivatives as a preventative measure against the onslaught of diseases and illnesses after exposure to dangerous materials.

More information: Thomas Rosenau, Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists, European Journal of Organic Chemistry, http://dx.doi.org/ … oc.201100178

Provided by Wiley (news : web)

Leicester researchers develop technologies to crack down on counterfeit whisky

Experts at the University of Leicester's Space Research Centre are working with colleagues at De Montfort University to create a handheld device which will detect fake whisky and wine – through the bottle.

The exciting research project to crack down on counterfeit whisky and wine is being supported by The Food and Drink iNet.

The technology has already been developed by the University of Leicester team to spot counterfeit medicines by scrutinising the packaging. Now the experts are working to transfer the technology to analyse liquids in bottles.

As well as helping to stamp out the big problem of counterfeit whisky and fine wine, this could also have major potential for airline security systems, they believe.

The technique relies on detecting the differences between the characteristics of light reflected from printed packaging. Originally developed from a spectrometer designed and built by the Space Research Centre for astronomical research, the technique was adapted for use in the pharmaceutical world by the University of Leicester team in conjunction with university spin-out firm Perpetuity Research and Consultancy International Limited which is a specialist crime and security consultancy.

Now the technology is being adapted again by the University of Leicester team for use in detecting fake liquids, with experts at De Montfort University providing skills in product design and rapid proto-typing so that a handheld device can be created.

“The support from the Food and Drink iNet will allow us to take the technology and apply it in the case of whisky and fine wines,” said Tim Maskell, Knowledge Transfer Manager in the Space Research Centre at the University of Leicester. “The iNet funding will enable us to design, build and test a laboratory prototype that will allow us to prove the technology works. If we can then take the technology and do something similar with other liquids there are potential airport security opportunities too.”

The project is one of five Collaborative Research and Development grants worth a total of more than L235,000 announced by the Food and Drink iNet, which co-ordinates innovation support for businesses, universities and individuals working in the food and drink sector in the East Midlands. The team has been awarded L50,000 towards the almost L71,000 cost of the research project.

Funded by East Midlands Development Agency (emda) and the European Regional Development Fund (ERDF), the Food and Drink iNet is one of four regional iNets that has developed an effective network to link academic and private sector expertise and knowledge with local food and drink business innovation needs.

“This is a fascinating research project between the University of Leicester, De Montfort University, the Scotch Whisky Research Institute and Leicestershire brewery Everards, which brings together space technology and the food and drink sector and offers real commercial benefit,” said Food and Drink iNet Director Richard Worrall. “Being able to test a liquid such as whisky or wine for authenticity without opening the bottle would bring major benefits to the drinks industry, as well as having opportunities in other fields, such as airport and airline security.

“The Food and Drink iNet Collaborative Research and Development programme is designed to provide help for innovative research schemes that will benefit the food and drink sector in the future, and this is one of the more interesting and beneficial.”

The team is working with The Scotch Whisky Research Institute and Leicestershire brewery Everards to help with the research and product trials.

The Food and Drink iNet aims to build on the tradition of innovation in the food and drink industry in the region by helping to create opportunities to develop knowledge and skills, and to help research, develop and implement new products, markets, services and processes. It is managed by a consortium, led by the Food and Drink Forum and including Food Processing Faraday, Nottingham Trent University, the University of Lincoln, and the University of Nottingham. It is based at Southglade Food Park, Nottingham, with advisors covering the East Midlands region.

Provided by University of Leicester (news : web)

Cancer drug found hiding in sunflower seed protein

University of Queensland scientists have found sunflower proteins and their processing machinery are hijacked to make rogue protein rings in a discovery that could open the door to cheaper, plant-based drug manufacturing.

Dr Joshua Mylne, who led the research, has a personal connection with sunflowers - his grandfather, Alan Lemon, introduced them to Australian farms, creating a multimillion-dollar industry.

Now, Dr Mylne hopes his research has uncovered another use for these plants through the manufacture of cheap therapeutic drugs.

Dr Mylne and Professor David Craik from UQ's Institute for Molecular Bioscience unpicked the way sunflower seeds assemble protein rings, one of which has previously demonstrated potential as a drug for cancer.

The study, published overnight in the international journal Nature Chemical Biology, showed that the machinery used to process and mature otherwise dull seed storage proteins is commandeered by a protein ring, SFTI, for its own use.

Dr Mylne and Professor Craik used the model plant Arabidopsis for their research, demonstrating that the sunflower protein production system could be moved into another species and thus SFTI could be manufactured in a range of plants.

While this work is of interest to researchers by providing an understanding of how new proteins can evolve and how proteins are matured, it has wider applications for drug production. SFTI can be used in its natural form to block breast cancer enzymes, and in a modified form to block enzymes associated with other types of cancer.

These proteins have not been broadly adopted by drug designers despite their potential to fight cancer because of the expense of producing them using traditional, synthetic manufacturing methods.

“Although SFTI and related proteins show great promise as drug templates, the cost to manufacture them is a significant barrier to widespread use,” Dr Mylne said.

“This issue could be solved through plant manufacturing. Seeds are an attractive system for the production of pharmaceuticals, as they are cheap to grow and their contents are stable at room temperature, and sterile inside their coat.

“There are also established systems in place for their production, harvest, storage and transportation, meaning they could be the ultimate low-cost drug delivery system.”

More information: http://dx.doi.org/ … NChemBio.542

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Researchers step closer to treatment of virulent hospital infection

Clostridium difficile is a health problem that affects hundreds of thousands of patients and costs $10 billion to $20 billion every year in North America. Researchers from the University of Calgary and the National Research Council of Canada say they are gaining a deeper understanding of this disease and are closer to developing a novel treatment using antibodies from llamas.

"We have found that relatively simple antibodies can interfere with the disease-causing toxins from C. difficile," says paper co-author Dr. Kenneth Ng, an associate professor of biological sciences at the University of Calgary and principal investigator of the Alberta Ingenuity Centre for Carbohydrate Science. "This discovery moves us a step closer to understanding how to neutralize the toxins and to create novel treatments for the disease." His research is part of a paper published today in the print issue of the Journal of Biological Chemistry.

Approximately two percent of all patients admitted to hospital may be infected by C. difficile, which thrives when healthy bacteria in the gut are weakened by antibiotics, thus allowing spores from Clostridium to germinate and colonize the large intestine.

"This research is significant because C. difficile is an increasing heath care problem and many people may experience multiple infections," says Dr. Glen Armstrong, head of the Department of Microbiology, Immunology, and Infectious Diseases in the Faculty of Medicine at the University of Calgary. "The current treatments are becoming less effective and C. difficile is developing resistance to conventional antibiotics. This research promises to provide a much-needed alternate treatment option that will overcome the failings of conventional antibiotics."

C. difficile produces two toxins -- toxin A (TcdA) and toxin B (TcdB) -- which cause damage to intestinal cells by binding to carbohydrates on the cell surface and disrupting cell functions such as adhesion. The new research shows that what's known as single-domain antibodies bind to the C. difficile toxins with high affinity and interfere with the toxins' ability to damage cells.

"Llamas have normal antibodies like our own, but they have also developed a second type of antibody with a simpler structure. It is this simpler structure that allows us to make modifications and perform many detailed studies that are not easily done with other types of antibodies," says Ng. "The unique characteristics of these single-domain antibodies provide an attractive approach for developing new treatments for C. difficile."

These single-domain antibodies were discovered in 1993 in camelids, which include llamas and camels. Camelids produce conventional antibodies found in all mammals as well as heavy-chain antibodies from which single-domain antibodies are derived. These single-chain antibodies are 10 times smaller than those found in humans and can be more readily engineered into a drug.

Dr. Jamshid Tanha, the corresponding author of the study from the National Research Council in Ottawa says that understanding how camelid antibodies work will ultimately allow researchers to develop a new treatment for this important disease and potentially others.

"We are currently working with Dr. Ng's group to determine why these antibodies are successful," says Tanha.

Currently, licensing opportunities with biotechnology firms are being explored.

More information: The article, Neutralization of Clostridium difficile toxin A with single-domain antibodies targeting the cell-receptor binding domain, is published in the Journal of Biological Chemistry http://www.jbc.org/

Provided by University of Calgary (news : web)

A 'check engine' light for the human body?

Imagine a sensor implanted in your body that signals when you're getting sick -- almost like the "check engine" light in a car. That scenario sounds like pure fantasy, but it may be closer to reality than many people think, according to an article in the current edition of Chemical & Engineering News (C&EN), ACS' weekly newsmagazine.

In the article, C&EN Associate Editor Britt E. Erickson describes one such medical device that's heading for clinical trials, perhaps later in 2011. It is a robotic arm that moves almost like a natural arm, thanks to a control system that monitors brain activity via a biosensor implanted on the surface of a patient's brain. That project aims to provide better artificial arms for wounded soldiers.

The article describes how scientists and medical device regulators are working together to fast track approval of such "biosensors" and devices. Biosensors monitor changes in the body, often "disease markers" — proteins, genes and other biochemical substances involved in health and disease. And they raise a red flag when things go awry. CEN points out that scientific advances will be important in tapping the full potential of biosensors. Scientists must find new disease markers, for instance, and better materials for making biosensors so they work for long periods while implanted in the body.

More information: "Biosensors on the Fast Track". This story is available at http://pubs.acs.or … 911gov2.html

Provided by American Chemical Society (news : web)

Sorted building blocks: Poly(propylene carbonate) stereogradient

The properties of polymers—long chain molecules from which plastics are made—depend on the type of individual building blocks in them, as well as the order they are in and how they are arranged in space. Although the order of the components can easily be controlled, control of their spatial arrangement, called stereochemistry, remains one of the biggest challenges in polymer chemistry. Kyoko Nozaki and a team from the University of Tokyo report in the journal Angewandte Chemie that they have made the first poly(propylene carbonate) with polymer chains built up in the form of a gradient of two stereochemically different propylene building blocks.

Poly(propylene carbonate) is used as a binding agent and as a component of biodegradable plastics. It is made from propylene oxide and carbon dioxide in a catalytic process. Propylene oxide contains three carbon atoms, two of which form a ring together with an oxygen atom. This ring opens during polymerization. Propylene oxide exists in two forms that are mirror images of each other; these are designated as the S and R stereoisomers.

Poly(propylene carbonate)s that are made primarily of one of the two forms or have both forms in an alternating pattern have been made before. Nozaki’s group has now been the first to synthesize both a stereoblock and a stereogradient. A stereoblock copolymer is a chain, half of which is made of the S form and the other half of the R form. In a stereogradient copolymer, the composition changes gradually from the S form to the R form.

Making a block copolymer is theoretically relatively easy because use of an asymmetric catalyst causes one of the two forms of building block to be used preferentially, so it is built into the polymer chains first; the less favorable form is incorporated afterward. In the case of poly(propylene carbonate), however, this process isn’t so trivial because once the favored form of the propylene oxide is converted to a polymer, the other form decomposes instead of polymerizing. The Japanese scientists found a special asymmetrical cobalt complex that allows nearly complete conversion to the polymer. Although the catalyst prefers the S form, it also ensures that it is more favorable for the R form to polymerize than to decompose.

The researchers experimented further with variations on the cobalt complex. A special ammonium side branch on a ligand brought success: It balances the degree of preference of the catalyst for the S form over the R form so that the R form begins to be incorporated into the polymer chain as the amount of the S form decreases. This allows the formation of the stereogradient copolymer. Interestingly, both of the new types of poly(propylene carbonate), stereoblock and stereogradient, are significantly more heat-tolerant than pure S or R polymers or mixtures of the two.

More information: Kyoko Nozaki, Synthesis of Stereogradient Poly(propylene carbonate) by Stereo- and Enantioselective Copolymerization of Propylene Oxide with Carbon Dioxide, Angewandte Chemie International Edition, http://dx.doi.org/ … ie.201007958

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Does selenium prevent cancer? It may depend on which form people take

Scientists are reporting that the controversy surrounding whether selenium can fight cancer in humans might come down to which form of the essential micronutrient people take. It turns out that not all "seleniums" are the same — the researchers found that one type of selenium supplement may produce a possible cancer-preventing substance more efficiently than another form of selenium in human cancer cells. Their study appears in the ACS' journal Biochemistry.

Hugh Harris and colleagues note that although the Nutritional Prevention of Cancer clinical trial showed that selenium reduced the risk of cancer, a later study called the Selenium and Vitamin E Cancer Prevention Trial did not show a benefit. A major difference between the trials was the form of selenium that was used. To find out whether different types of selenium have different chemopreventive properties, the researchers studied how two forms—SeMet and MeSeCys—are processed in human lung cancer cells.

The researchers found that MeSeCys killed more lung cancer cells than SeMet did. Also, lung cancer cells treated with MeSeCys processed the selenium differently than than cells treated with SeMet. They say that these findings could explain why studies on the health benefits of selenium sometimes have conflicting results.

Provided by American Chemical Society (news : web)