Anti-malaria drug synthesized with the help of oxygen and light

There is an effective treatment against malaria, but it is not accessible to all of the more than 200 million people worldwide who are affected by the disease. Millions, especially in the developing world, cannot afford the combination drug preparation, which consists mainly of artemisinin. Moreover, the price for the medication varies, as this substance is isolated from sweet wormwood (Artemisia annua) which grows mainly in China and Vietnam, and varies seasonally in its availability. To make the drug affordable for at least some patients in developing countries, the Clinton Foundation, for example, subsidises its cost to the tune of several million dollars per year. Nevertheless, over one million people die of malaria each year because they do not have access to effective drugs.

This may be about to change. Peter H. Seeberger, Director at the Max Planck Institute of Colloids and Interfaces in Potsdam and Professor of Chemistry at the Freie Universität Berlin and his colleague François Lévesque have discovered a very simple way of synthesising the artemisinin molecule, which is known as an anti-malaria drug from traditional Chinese medicine and has an extremely complex chemical structure. "The production of the drug is therefore no longer dependent on obtaining the active ingredient from plants," says Peter Seeberger.

Synthesis from a by-product of artemisinin production

As a starting point, the chemists use artemisinic acid – a substance produced as a hitherto unused by-product from the isolation of artemisinin from sweet wormwood, which is produced in volumes ten times greater than the active ingredient itself. Moreover, artemisinic acid can easily be produced in genetically modified yeast as it has a much simpler structure. "We convert the artemisinic acid into artemisinin in a single step," says Peter Seeberger. "And we have developed a simple apparatus for this process, which enables the production of large volumes of the substance under very controlled conditions." The only reaction sequence known up to now required several steps, following each of which the intermediate products had to be isolated laboriously – a method that was far too expensive to offer as a viable alternative to the production of the drug from plants.

The striking simplification of artemisinin synthesis required not only a keen sense for an elegant combination of the correct partial reactions to enable the process to take place in a single step; it also took a degree of courage, as the chemists departed from the paths typically taken by industry up to now. The effect of the molecule, which not only targets malaria but possibly also other infections and even breast cancer, is due to, among other things, a very reactive chemical group formed by two neighbouring oxygen atoms – which chemists refer to as an endoperoxide. Peter Seeberger and François Lévesque use photochemistry to incorporate this structural element into the artemisinic acid. Ultraviolet light converts oxygen into a form that can react with molecules to form peroxides.

800 photoreactors should suffice to cover the global requirement for artemisinin

"Photochemistry is a simple and cost-effective method. However, the pharmaceutical industry has not used it to date because it was so difficult to control and implement on a large scale," explains Peter Seeberger. In the large reaction vessels with which industrial manufacturers work, flashes of light do not penetrate deeply enough from outside and the reactive form of oxygen is not produced in sufficient volumes. The Potsdam-based scientists have succeeded in resolving this problem using an ingenious trick: They channel the reaction mixture containing all of the required ingredients through a thin tube that they have wrapped around a UV lamp. In this structure, the light penetrates the entire reaction medium and triggers the chemical conversion process with optimum efficiency.

"The fact that we do not carry out the synthesis as a one-pot reaction in a single vessel, but in a continuous-flow reactor enables us to define the reaction conditions down to the last detail," explains Peter Seeberger. After just four and a half minutes a solution flows out of the tube, in which 40 percent of the artemisinic acid has become artemisinin.

"We assume that 800 of our simple photoreactors would suffice to cover the global requirement for artemisinin," says Peter Seeberger. And it could all happen very quickly. Peter Seeberger estimates that the innovative synthesis process could be ready for technical use in a matter of six months. This would alleviate the global shortage of artemisinin and exert considerable downward pressure on the price of the associated drugs.

More information: François Lévesque and Peter H. Seeberger, Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin, Angewandte Chemie International Edition, 16 January 2012; DOI: 10.1002/anie.201107446

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

Computer simulations give insights into how carbon dioxide reacts with a sequestering liquid

This work by Dr. Liem X. Dang and Dr. Tsun-Mei Chang is featured in an invited perspectives article in The Journal of Physical Chemistry Letters. A perspective article provides state-of-the-art research on new and emerging areas by leaders in the field. An image from the team's study graced the journal's cover.

While it might seem like an esoteric topic, useful only to those who inhabit ivory towers, understanding how gases interact with a liquid surface influences a lot, including the air we breathe and the energy we use. For example, coal-fired power plants produce large amounts of carbon dioxide. Scientists and industry leaders want to remove that dioxide and prevent its access to the environment. One option is to pump the gas through a liquid that traps only the carbon dioxide, and not other gases. But to do it, scientists must know how the gas interacts with the liquid's surface.

"If we want to optimize gas sorption, we must understand the interface, because most of the chemical and physical processes usually occur at the interface," said Dang.

When the reaction speed is measured in trillionths of a second and at scales measured in the width of atoms, scientists turn to powerful computer simulations to understand what is happening. The simulations allow them to freeze the action and gather accurate data. The researchers focused on gaseous carbon dioxide and a more hydrophobic or water-fearing room-temperature ionic liquid (see sidebar) known as [bmim][Tf2N].

The accuracy of that data depends in part on how well the molecular interactions, molecular orientation and surface tension are described. The research duo began by thoroughly examining the models, creating accurate portrayals.

Then, the team ran a series of simulations and examined how the gas and the liquid interacted. They found the solubilities of gases are critically dependent on the type of anions or negatively charged ions used to construct the ionic liquids.

"Solubilities are an active research subject in the ionic liquids field," said Dang.

The results raise questions about whether or not polarizable models are needed to simulate ionic liquids. This and questions about the influence of different charged particles in the liquid are being studied by the researchers.

More information: LX Dang and TM Chang. 2012. "Molecular Mechanism of Gas Adsorption into Ionic Liquids: A Molecular Dynamics Study." The Journal of Physical Chemistry Letters 3(2): 175-181. DOI: 10.1021/jz2011786

Provided by Pacific Northwest National Laboratory (news : web)

Chemists unlock potential target for drug development

A team led by Dana Spence of MSU's Department of Chemistry has revealed a way to isolate and test the receptor known as P2X1. By creating a new, simple method to study it after blood is drawn, the team has unlocked a potential new drug target for many diseases that impact red blood cells, such as diabetes, hypertension and cystic fibrosis.

Researchers can evaluate the receptor not only in developing new drugs but also re-testing existing medications that could work now by attaching to the receptor.

"Scientists are always looking for new 'druggable' receptors in the human body," Spence said. "This receptor, P2X1, has long been viewed as not important in platelets; our studies show that is not necessarily true. The receptor is very active; you just need to be careful in working with it."

The research is published in the current issue of Analytical Methods, a journal from the Royal Society of Chemistry in London.

The main job of platelets is to help prevent bleeding via clotting, Spence said. They work by getting sticky in the bloodstream, but the problem with some diseases such as diabetes or sickle-cell anemia is that the platelets get sticky even when they shouldn't, preventing proper blood flow and blocking vessels.

Platelets are activated when their receptors are "turned on"; currently, researchers have always focused on the P2Y receptor, which is easily studied. On the other hand, the P2X1 receptor was not thought to play a major role in platelet activation, and it proved very troublesome to study since it became desensitized once blood is drawn from the body, Spence said.

Though scientists tried a pair of methods to get around that issue – by using different additives or enzymes – the results did not prove fruitful in studying the receptor.

What Spence and his team found is that by adding a simple molecule called NF449 – originally thought to block the receptor – they were able to activate the P2X1 receptor in platelets after a blood draw.

"We have discovered a way to prepare and handle platelets so that we can study the receptor authentically," he said. "This research opens up new avenues of study and will allow researchers and pharmaceutical companies to re-appraise this receptor as a druggable target."

More information: The research paper can be found at Analytical Methods at http://pubs.rsc.or … y/c1ay05530e

Provided by Michigan State University (news : web)

Small things, big thinking

From molecules to jungles, biological systems grow themselves. This natural hierarchical self-assembly process, which operates simultaneously on many scales, fascinates Dr Chris Forman, an Associate Researcher at Cambridge University’s Institute for Manufacturing. Having trained as a theoretical physicist and worked in satellite communications, he decided to concentrate his research efforts on sustainability and to look at how academic disciplines could work together to unlock some of the mysteries that lie behind the staggeringly complex processes in biology.

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Forman is one of the contributors to a new series of online videos titled Under the Microscope produced by the University of Cambridge.  These one-minute videos capture glimpses of the natural and man-made world seen in stunning close-up and convey the excitement of cutting-edge science in areas that range from beetle eyes to killer T-cells, from nano-wires to fish skeletons. Each one is accompanied by an explanatory voiceover from the scientist involved, who talks about his or her research and how it might impact on society. The series will appear twice a week on the Cambridge University website.

In choosing to focus on images of fruit flies and beetle antenna Forman draws attention to the extraordinary structures found in the ordinary organisms – and encourages us to look deep into their structure and function to see how they are fine tuned to tasks that help them to thrive and survive. “I wanted something with a big yuck factor to show the remarkable level of integration that exists in the natural world,” he says.  “On a nano-scale the beetle’s eye and the fly’s foot reveal a stunning complexity that simply eludes current manufacturing.  And close-up images of bugs grab the attention of children and adults marvellously.”

Forman works mostly at the level of individual molecules – his PhD focused on the prospect of transporting electrons along self-assembled protein fibres, not unlike spider silk – but he also keeps a close eye on the big picture of larger scale structures and processes to guide his work.  Perhaps the best example of this interplay between processes at very different length scales concerns the natural levels of carbon dioxide in the atmosphere.  The natural balance of CO2 arises to a large extent from repeating the same chemical reactions trillions upon trillions of times around the planet in living cells, and the precise details of those chemical reactions are determined mostly by the sequence of information in genes.

His vision is that, by understanding molecular self-assembly and mixing this with the ability to perform arbitrary chemistry, we could make radically diverse structures for many purposes from the same restricted set of materials as natural systems. This would make it easier for each local community to be in balance with its immediate environment while achieving its economic goals, and sharing the knowledge of how to do this around the world could allow a global harmony to emerge naturally, one molecule at a time.  Such visionary holistic ideas are just one aspect of the fast-developing field known as biomimetics.

While some of Forman’s work is based on making connections between existing fields of science, much of it could be described as leaps of the imagination. By thinking a stage beyond what we already know, he is working on ideas that may not see fruition for 20 years – or may indeed evolve into unforeseen directions.  “As university researchers we have the freedom to think about such blue sky prospects without some of the restrictions that apply when you are working in the commercial or public sector. In particular, at Cambridge we are also able to move more easily between sectors by virtue of the collegiate system,” he says. “The more I study the natural world, the more impressed I am by what it can teach us about molecular organisation. I want to inspire the thinkers and leaders of the future who will take the knowledge discovered in universities and apply it in the commercial and political worlds.”

The world’s resources are under huge pressure from an expanding human population. Transport is a big user of energy and manufacturing processes rely heavily on transport.  As Forman puts it: “Industry depends on large lumps of materials being moved from process to process – often across the planet.” He asked himself a simple question: what would happen if we eliminated all methods of transport? “If you can’t travel, you have to do everything in one place: raw material extraction, manufacturing, assembly, consumption and recycling. Is there anything that can do this already? Yes – it’s called a tree! A tree gets it nutrients, it grows and dies. As it decays it releases its nutrients thereby nurturing the myriad of creatures that use it as an environment.  A tree does all this without moving from where it takes root -and it’s solar powered. While we can’t make everything from trees we can get construction materials, textiles and food which represent the bulk of our basic needs.  Perhaps in the future we will be able to extract even more than this from artificial static systems designed to emulate and fit in with the local natural ecology.”

All organisms are made from the same basic materials – carbon, hydrogen, oxygen and so on. What drives them to grow, and what makes them so amazingly diverse, is the information stored in their genes and the compartmentalisation that provides a context to that information.  “Take a mushroom, a tree and a pig. They appear completely different but they all use DNA, proteins, lipids etc. All have the ability to grow but they grow in markedly different ways, which depends strongly on their local environment.  In looking at how these fundamental forces interact at all length scales we are looking both at global environmental factors and the quantum processes in individual molecular interactions that we are only just beginning to grasp. It is a global system with quantum resolution and each of us is part of that system,” says Forman.

“A living biological cell is basically a complex network of chemical reactions contained inside a little bag. Can we emulate this process and replicate it? Maybe by compressing our processes into small packages and distributing them all over we can do all our recycling and manufacturing in our houses, rather than in factories with lorries moving large lumps of stuff about?  In this way we get more control as individuals over what we want and how it’s made. This could be better for both the environment and the economy – as it gives all seven billion of us the same chance to add value to our lives locally, which is considerably more value than currently exists in the world.”

Forman believes that science might one day enable us to create products as complex as IPods and computers in our living rooms – designed for our own immediate needs and made from local material.  Currently, industrial sectors such as energy, textiles, food and high-tech electronics are all looking at how to copy or exploit nature in many ways.  In the energy sector viruses and enzymes are being used to organise batteries or capture solar energy. Sectors such as food and textiles are already biologically-based. In hi-tech electronics people are looking at using organic molecular-based electronics to create next generation flexible displays. “Perhaps these radically different sectors should consider joining forces to learn how they can benefit In terms of optimal use of resources at the molecular scale.  Imagine a cake that displayed an edible temporary video screen? Imagine being able to make such a cake in your own kitchen? It’s conceivable that the commercial battles of the future will take place inside artificial cells in the walls of our houses rather than on the shelves of the supermarkets.”

The ultimate goal is to achieve a closed loop economy – a system that is self-sustaining with respect to material, in which the same material loops around and around the economy and is endlessly powered by sunlight alone. On each cycle the precise form and function of the material is determined solely by the individual for whatever purpose they have need of there and then, and the job of industry and regulation is to enable them to do it harmlessly.   One way of achieving such a closed loop is to create what is known as an industrial ecology, in which companies trade waste for mutual benefit. The best known example is the city of Kalundborg in Denmark, in which industries as diverse as energy, plaster-board manufacturing, road construction and pig-farming have collaborated to achieve economic and ecological efficiency.

By shrinking a city-wide industrial ecology into a volume the size of a cell, the need to transport raw materials and products over long distances is removed, and the energy required to process the material is reduced to the point where sunlight can be used directly. We know the range of species that can be produced with biological cells; if we are able to harness similar processes we may open up a huge array of possibilities.  But how far can we take this idea technologically?  Forman is keen to communicate these ideas to the public to acquire their input before it is fully explored scientifically and has devised a talk called “Can iPods grow on trees?”  He says: “The idea behind it isn’t as nuts as it sounds.  Every component in an iPod has a biological analogue.   To give one example: just as you can upload a tune to play on your IPod, so the lyre bird has learned to reproduce any sound it hears perfectly. Nature is an inspiring teacher.”

Provided by University of Cambridge (news : web)