Saturday, January 14, 2012

Record reaction cascade yields cancer drug candidate

The of complex molecules is often laborious and time-consuming. To produce such molecules, usually have to carry out numerous individual processes in sequence and isolate the intermediate products each time until they finally obtain the desired end product. In contrast, reaction cascades lead to the end product considerably faster: because they involve a kind of , it is sufficient to provide the starting materials and initiate the first step to reach the end product via a series of successive intermediate products and steps. Because the entire cascade takes place in a single reaction vessel, the isolation of intermediate products is dispensed with and the process saves time, energy and costs.

A team of scientists working with Herbert Waldmann, Director at the Max Planck Institute of in Dortmund has now succeeded in developing the longest reaction cascade known up to now. The researchers used it to synthesise biologically active substances termed Centrocountins in twelve individual steps: Centrocountins are complex molecules which intervene in cell division and prompt to commit .

“This process holds the current world record for cascade length,” says Kamal Kumar, a scientist at the Max Planck Institute in Dortmund who made a decisive contribution to the development of the synthesis process. The reaction begins with simple tryptamine derivatives and incorporates nine different individual reactions over twelve steps, which involve the use of two different catalytic mechanisms. The end products have a complex molecular structure with four ring systems. The entire reaction takes between ten and 30 minutes. “The production of of this complexity using traditional methods would take days if not weeks,” says Kamal Kumar.

As tests on cell cultures showed, cells treated with Centrocountins did not divide in two but in three or more daughter cells which were not viable. The effect is due to the fact that the substances bind to certain proteins – nucleophosmin (NPM) and Crm1 – which play an important role in the formation of the spindle apparatus and organelles known as centrosomes, which provide starting points for the spindle apparatus. These structures ensure the correct separation of the chromosomes between the two daughter cells during cell division. As a result of treatment with Centrocountins, a dividing cell has multiple spindles poles instead of two. –. As a result, the cell can no longer correctly count its centrosomes – hence the name “Centrocountin”. The chromosomes are unable to orient themselves correctly at the metaphase plate and the cell division cycle comes to a standstill. The cell can only divide when all chromosomes are correctly arranged. The daughter cells produced in this way are not viable.

Due to their central role in , the two proteins NPM and Crm1 are identified as potential molecular targets for cancer treatment. “An active substance that binds to both NPM and Crm1 has not been available up to now,” says Slava Ziegler, a scientist at the Max Planck Institute in Dortmund who played a leading role in the identification of the target proteins. Hence, the new Centrocountins provide a promising starting point for the development of new tumour therapies.

More information: Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Alexander W. Bird, Zoltan Maliga, Andreas Brockmeyer, Petra Janning, Anthony Hyman, Stefan Grimme, Markus Schürmann, Hans Preut, Katja Hübel, Slava Ziegler, Kamal Kumar und Herbert Waldmann, Natural Product-Inspired Cascade Synthesis Yields Modulators of Centrosome Integrity, Nature Chemical Biology.

Provided by Max-Planck-Gesellschaft (news : web)

Nanocrystals make dentures shine

The hardest substance in the is moved by its strongest muscles: When we heartily bite into an apple or a schnitzel, enormous strengths are working on the surface of our teeth. "What the natural has to endure also goes for dentures, inlays or bridges", glass chemist Prof. Dr. Dr. Christian Rüssel of the Friedrich Schiller University Jena (Germany) says. After all, these are worn as much as healthy teeth. Ceramic materials used so far are not very suitable for bridges, as their strengths are mostly not high enough. Now Prof. Rüssel and his colleagues of the Otto-Schott-Institute for Glass Chemistry succeeded in producing a new kind of glass ceramic with a nanocrystalline structure, which seems to be well suited to be used in dentistry due to their high strength and its optical characteristics. The glass chemists of Jena University recently published their research results in the online-edition of the science magazine Journal of Biomedical Materials Research.

Glass-ceramics on the basis of magnesium-, aluminium-, and silicon oxide are distinguished by their enormous strength. "We achieve a strength five times higher than with comparable denture ceramics available today", Prof. Rüssel explains. The Jena glass chemists have been working for a while on high density ceramics, but so far only for utilisation in other fields, for instance as the basis of new efficient computer hard drives. "In combination with new an additional field of application is opening up for these materials in ", Prof. Rüssel is convinced.

Materials, to be considered as dentures are not supposed to be optically different from natural . At the same time not only the right colour shade is important. "The enamel is partly translucent, which the ceramic is also supposed to be", Prof. Rüssel says.

To achieve these characteristics, the glass-ceramics are produced according to an exactly specified temperature scheme: First of all the basic materials are melted at about 1.500 °C, then cooled down and finely cut up. Then the glass is melted again and cooled down again. Finally, nanocrystals are generated by controlled heating to about 1,000 °C. "This procedure determines the crystallisation crucial for the strength of the product", the glass chemist Rüssel explains. But this was a technical tightrope walk. Because a too strongly crystallised material disperses the light, becomes opaque and looks like plaster. The secret of the Jena ceramic lies in its consistence of nanocrystals. The size of these is at most 100 nanometers in general. "They are too small to strongly disperse light and therefore the ceramic looks translucent, like a natural tooth", Prof. Rüssel says.

A lot of developing work is necessary until the from the Jena Otto-Schott-Institute will be able to be used as dentures. But the groundwork is done. Prof. Rüssel is sure of it.

More information: Dittmer M, Rüssel C.: Colorless and high strength MgO/Al2O3/SiO2 glass-ceramic dental material using zirconia as nucleating agent. J Biomed Mater Res B Appl Biomater. 2011 Nov 21. doi: 10.1002/jbm.b.31972

Provided by Friedrich-Schiller-Universitaet Jena

Researchers discover one of the most porous materials to date

Working with metal-organic frameworks—crystalline compounds comprising metal- cluster vertices linked together by organic molecules to form one-, two-, or three-dimensional porous structures—researchers addressed changing the size of the vertex (the metal cluster) rather than the length of the organic molecule links, which resulted in the largest metal organic framework pore volume reported to date.

"Think of this the way you imagine Tinkertoys®," said Nathaniel Rosi, principal investigator and assistant professor in Pitt's Department of Chemistry in the Dietrich School. "The metal clusters are your joints, and the organic molecules are your linkers. In order to build a highly open structure with lots of empty space, you can increase the linker length or you can increase the size of the joint. We developed chemistry to make large joints, or vertices, and showed that we could link these together to build a material with extraordinarily large pores for this class of materials.

"Essentially, we're like architects. We first make a blueprint for a target material, and we then select our building blocks for construction," added Rosi. "We develop methods for designing structures and controlling the assembly of these structures on a molecule-by- molecule basis."

Rosi and Jihyun An, who graduated with a PhD degree in chemistry from Pitt in 2011 and is lead author of the paper, said this new approach could have an impact on storing large quantities of gas such as carbon dioxide or methane, an important development for alternative energy, or large amounts of drug molecules, which could impact the drug-delivery field. Since joining Pitt five years ago, Rosi has developed a lab that includes students and postdoctoral researchers from various chemistry-related disciplines and focuses on new methods for materials' design and discovery.

Provided by University of Pittsburgh

Foam bubbles finally brought to order

In 1994, Denis Weaire and Robert Phelan of Trinity College Dublin’s School of Physics made a landmark discovery in physics, and created a new ideal structure of foam.  It is the most efficient way to partition space into equal volume cells while minimising surface area – something soap bubbles strive to do in nature.   Their geometry of soap bubbles improved on a previous principle devised by the physicist, Lord Kelvin a century ago.

The Weaire-Phelan structure consists of two kinds of polyhedral bubbles with twelve and fourteen sides respectively. The structure can be cut along planes, showing the existence of layers of bubbles. Since its introduction in 1994 it has played an important role in theory and simulation of foams, for example in the study of elastic properties.

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The structure went on to inspire the design of the 2008 Olympic Games' iconic building, the Water Cube in the National Aquatic Center in Beijing.  Many millions have admired its elegant framework of steel beams, which follow the pattern of the ideal foam.

The physicists have now gone a step further and this month succeeded in turning the mathematical concept into real foam.

Now it exists in reality, thanks to the work of a team led by Dr. Ruggero Gabbrielli, from the University of Trento, in an SFI-funded visit to Trinity College.  Back in 1994 while the concept was computed, with the help of the software by Kenneth Brakke, they were unable to fabricate the new foam.

Acknowledging that the previous failures could be put down to the shape of the containers used, Gabbrielli along with Brakke designed a receptacle whose walls had an intricate form that would encourage and accommodate the Weaire-Phelan bubbles.  It was made in Trinity’s nanoscience institute, CRANN  and proved an instant success when of the right size were introduced into it.

“Wonderful!” says Weaire, now an Emeritus Professor in the School of Physics. “We shall call this the Italian Job.  It opens up a lot of further possibilities.”

In response to whether the new foam could be of any practical use: “Not immediately”, says Professor Stefan Hutzler, Head of the Foams and Complex Systems Research group in the School of Physics. “Let’s just admire its extraordinary beauty first.  But in solidified form and on various scales, such exotic ordered foams could find applications as chemical filters, heat exchangers and optical components.”

“It’d be interesting to come up with a proof of optimality,” Ruggero says.  “Scientists have been looking at this problem for quite a while, but a rigorous result is still missing.”

The paper reporting the fabrication of the Weaire-Phelan structure was accepted for publication in the time-honored science journal Philosophical Magazine Letters on the 25th of November 2011.  This is the same journal in which both Kelvin (in 1887) and Weaire and Phelan (in 1993) published their work on the of ideal foam.

Provided by Trinity College Dublin (news : web)