Chemists devise chemical reaction that holds promise for new drug development

A team of researchers at the California Institute of Technology (Caltech) has devised a new method for making complex molecules. The reaction they have come up with should enable chemists to synthesize new varieties of a whole subclass of organic compounds called nitrogen-containing heterocycles, thus opening up new avenues for the development of novel pharmaceuticals and natural products ranging from chemotherapeutic compounds to bioactive plant materials such as morphine.

The team -- led by Brian Stoltz, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry, and Doug Behenna, a scientific researcher -- used a suite of specialized robotic tools in the Caltech Center for Catalysis and Chemical Synthesis to find the optimal conditions and an appropriate catalyst to drive this particular type of reaction, known as an alkylation, because it adds an alkyl group (a group of carbon and hydrogen atoms) to the compound. The researchers describe the reaction in a recent advance online publication of a paper in Nature Chemistry.

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," Stoltz says. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access."

The reaction creates compounds called heterocycles, which involve cyclic groups of carbon and nitrogen atoms. Such nitrogen-containing heterocycles are found in many natural products and pharmaceuticals, as well as in many synthetic polymers. In addition, the reaction manages to form carbon-carbon bonds at sites where some of the carbon atoms are essentially hidden, or blocked, by larger nearby components.

"Making carbon-carbon bonds is hard, but that's what we need to make the complicated structures we're after," Stoltz says. "We're taking that up another notch by making carbon-carbon bonds in really challenging scenarios. We're making carbon centers that have four other carbon groups around them, and that's very hard to do."

The vast majority of pharmaceuticals being made today do not include such congested carbon centers, Stoltz says -- not so much because they would not be effective compounds, but because they have been so difficult to make. "But now," he says, "we've made it very easy to make those very hindered centers, even in compounds that contain nitrogen. And that should give pharmaceutical companies new possibilities that they previously couldn't consider."

Perhaps the most important feature of the reaction is that it yields almost 100 percent of just one version of its product. This is significant because many organic compounds exist in two distinct versions, or enantiomers, each having the same chemical formula and bond structure as the other, but with functional groups in opposite positions in space, making them mirror images of each other. One version can be thought of as right-handed, the other as left-handed.

The problem is that there is often a lock-and-key interaction between our bodies and the compounds that act upon them -- only one of the two possible hands of a compound can "shake hands" and fit appropriately. In fact, one version will often have a beneficial effect on the body while the other will have a completely different and sometimes detrimental effect. Therefore, it is important to be able to selectively produce the compound with the desired handedness. For this reason, the FDA has increasingly required that the molecules in a particular drug be present in just one form.

"So not only are we making tricky carbon-carbon bonds, we're also making them such that the resulting products have a particular, desired handedness," Stoltz says. "This was the culmination of six years of work. There was essentially no way to make these compounds before, so to all of a sudden be able to do it and with perfect selectivity… that's pretty awesome."

In addition to Stoltz and Behenna, other authors on the paper, "Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams," include Yiyang Liu, Jimin Kim, David White, and Scott Virgil of Caltech, and Taiga Yurino, who visited the Stoltz lab on a fellowship supported by the Japan Society for the Promotion of Science. The work was supported by the King Abdullah University of Science and Technology, the NIH-NIGMS, the Gordon and Betty Moore Foundation, Amgen, Abbott, and Boehringer Ingelheim.

Story Source:

The above story is reprinted from materials provided by California Institute of Technology. The original article was written by Kimm Fesenmaier.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Douglas C. Behenna, Yiyang Liu, Taiga Yurino, Jimin Kim, David E. White, Scott C. Virgil, Brian M. Stoltz. Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams. Nature Chemistry, 2011; DOI: 10.1038/nchem.1222

Bucky balls for next-generation spintronics devices

The beauty of an electron's spin is that it responds very rapidly to small magnetic fields. Such external magnetic fields can be used to reverse the direction of spin. In this way, information can be carried by a flow of electrons. For instance, electrons with a left-hand spin could represent a "1," and those with a right-hand spin, a "0." It takes less time to flip the spin direction than it does to switch a current on or off. Accordingly, spintronics could potentially be very fast and extremely compact.

Organic materials

However, this would require a material that combines the characteristics of a semiconductor (such as silicon, the most widely used material in the chip industry) with magnetic properties. Research in this area (including work by Michel de Jong) has already delivered results. However, finding materials with this combination of properties is far from simple. For this reason, Michel de Jong is now hunting for an alternative. He is focusing on semiconductors consisting of carbohydrate chains, in other words, organic materials. "Such materials are already being used in the displays of the latest smart phones. Indeed, they are very much the 'in' thing. I expect it will ultimately be possible to make very cheap electronics from these materials, leading to a wide range of new applications. For instance, if supermarkets want to tag their products with pricing information, then the electronics involved will have to cost next to nothing."

Buckyballs

De Jong has been experimenting with buckyballs (spherical C60 molecules held together by weak bonds) sandwiched between two magnetic materials. "The great advantage of these molecules is that they have very little effect on electron spin. This enables them to store spin information for much longer periods of time than silicon." Depending on the orientation of the magnetic field in the upper and lower layers of magnetic material, electrons with the same direction of spin are either allowed through or held back, as if a valve were being opened or closed. This would make it possible to create sensitive magnetic sensors, for example. The "sandwich" might also form the basis for new electronic components that make use of spin.

"If we are to make truly effective components, we will need a detailed understanding of events at the interface between the magnetic and organic materials. However, this will require improvements in the quality of such interfaces. The current techniques for applying metallic layers to organic layers do not produce good interconnections. The organic material contains cavities that can fill with metal. This results in unpredictable behaviour. Over the next five years we will be seeking to improve the manufacturing process. This will help us to understand what exactly happens at the interface."

Story Source:

The above story is reprinted from materials provided by University of Twente, via AlphaGalileo.

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The perfect liquid -- now even more perfect

How liquid can a fluid be? This is a question particle physicists at the Vienna University of Technology have been working on. The "most perfect liquid" is nothing like water, but the extremely hot quark-gluon-plasma which is produced in heavy-ion collisions at the Large Hadron Collider at CERN. New theoretical results at Vienna UT show that this quark-gluon plasma could be even less viscous than was deemed possible by previous theories.

The results were published in Physical Review Letters and highlighted as an "editors' selection."

Liquids and their Viscosity

Highly viscous liquids (such as honey) are thick and have strong internal friction, quantum liquids, such as super fluid helium can exhibit extremely low viscosity. In 2004, theorists claimed that quantum theory provided a lower bound for viscosity of fluids. Applying methods from string theory, the lowest possible ratio of viscosity to the entropy density was predicted to be h/4? (with the Planck-constant h). Even super fluid helium is far above this threshold. In 2005, measurements showed that quark-gluon-plasma exhibits a viscosity just barely above this limit. However, this record for low viscosity can still be broken, claims Dominik Steineder from the Institute for Theoretical Physics at Vienna UT. He obtained this remarkable result working as a PhD-student with Professor Anton Rebhan.

Black Holes and Particle Collisions

The viscosity of a quark-gluon plasma cannot be calculated directly. Its behavior is so complicated that very sophisticated tricks have to be applied, says Anton Rebhan: "Using string theory, the quantum field theory of quark-gluon plasma can be related to the physics of black holes in higher dimensions. So we are solving equations from string theory and then transfer the results to the physics of the quark-gluon plasma." The previously established lower bound for viscosity was calculated in a very similar way. However, in these calculations the plasma was modeled to be symmetric and isotropic. "In fact, a plasma produced by a collision in a particle accelerator is not isotropic at the beginning," says Anton Rebhan. The particles are accelerated and collided along one specific direction -- so the resulting plasma shows different properties, depending on the direction from which one looks at it.

Breaking the Limits

The physicists at Vienna UT found a way to include this anisotropy in their equations -- and surprisingly the limit for the viscosity can be broken in this new model. "The viscosity depends on several other physical parameters, but it can be lower than the number previously considered to be the absolute lower bound," Dominik Steineder explains. The on-going quark-gluon-experiments at CERN will provide opportunities for testing the new theoretical predictions.

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The above story is reprinted from materials provided by Vienna University of Technology, TU Vienna, via AlphaGalileo.

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Journal Reference:

Anton Rebhan, Dominik Steineder. Violation of the Holographic Viscosity Bound in a Strongly Coupled Anisotropic Plasma. Physical Review Letters, 2012; 108 (2) DOI: 10.1103/PhysRevLett.108.021601

Easier testing for diabetics? Biochip measures glucose in saliva, not blood

Engineers at Brown University have designed a biological device that can measure glucose concentrations in human saliva. The technique could eliminate the need for diabetics to draw blood to check their glucose levels. The biochip uses plasmonic interferometers and could be used to measure a range of biological and environmental substances. 

For the 26 million Americans with diabetes, drawing blood is the most prevalent way to check glucose levels. It is invasive and at least minimally painful. Researchers at Brown University are working on a new sensor that can check blood sugar levels by measuring glucose concentrations in saliva instead.

The technique takes advantage of a convergence of nanotechnology and surface plasmonics, which explores the interaction of electrons and photons (light). The engineers at Brown etched thousands of plasmonic interferometers onto a fingernail-size biochip and measured the concentration of glucose molecules in water on the chip. Their results showed that the specially designed biochip could detect glucose levels similar to the levels found in human saliva. Glucose in human saliva is typically about 100 times less concentrated than in the blood.

"This is proof of concept that plasmonic interferometers can be used to detect molecules in low concentrations, using a footprint that is ten times smaller than a human hair," said Domenico Pacifici, assistant professor of engineering and lead author of the paper published in Nano Letters, a journal of the American Chemical Society.

The technique can be used to detect other chemicals or substances, from anthrax to biological compounds, Pacifici said, "and to detect them all at once, in parallel, using the same chip."

To create the sensor, the researchers carved a slit about 100 nanometers wide and etched two 200 nanometer-wide grooves on either side of the slit. The slit captures incoming photons and confines them. The grooves, meanwhile, scatter the incoming photons, which interact with the free electrons bounding around on the sensor's metal surface. Those free electron-photon interactions create a surface plasmon polariton, a special wave with a wavelength that is narrower than a photon in free space. These surface plasmon waves move along the sensor's surface until they encounter the photons in the slit, much like two ocean waves coming from different directions and colliding with each other. This "interference" between the two waves determines maxima and minima in the light intensity transmitted through the slit. The presence of an analyte (the chemical being measured) on the sensor surface generates a change in the relative phase difference between the two surface plasmon waves, which in turns causes a change in light intensity, measured by the researchers in real time.

"The slit is acting as a mixer for the three beams -- the incident light and the surface plasmon waves," Pacifici said.

The engineers learned they could vary the phase shift for an interferometer by changing the distance between the grooves and the slit, meaning they could tune the interference generated by the waves. The researchers could tune the thousands of interferometers to establish baselines, which could then be used to accurately measure concentrations of glucose in water as low as 0.36 milligrams per deciliter.

"It could be possible to use these biochips to carry out the screening of multiple biomarkers for individual patients, all at once and in parallel, with unprecedented sensitivity," Pacifici said.

The engineers next plan to build sensors tailored for glucose and for other substances to further test the devices. "The proposed approach will enable very high throughput detection of environmentally and biologically relevant analytes in an extremely compact design. We can do it with a sensitivity that rivals modern technologies," Pacifici said.

Tayhas Palmore, professor of engineering, is a contributing author on the paper. Graduate students Jing Feng (engineering) and Vince Siu (biology), who designed the microfluidic channels and carried out the experiments, are listed as the first two authors on the paper. Other authors include Brown engineering graduate student Steve Rhieu and undergraduates Vihang Mehta, Alec Roelke.

Results are published in Nano Letters. The National Science Foundation and Brown (through a Richard B. Salomon Faculty Research Award) funded the research.

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The above story is reprinted from materials provided by Brown University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Jing Feng, Vince S. Siu, Alec Roelke, Vihang Mehta, Steve Y. Rhieu, G. Tayhas R. Palmore, Domenico Pacifici. Nanoscale Plasmonic Interferometers for Multispectral, High-Throughput Biochemical Sensing. Nano Letters, 2012; 120109130837001 DOI: 10.1021/nl203325s