Category Archives: Chemistry

As we were collecting reactions from The Synaptic Leap for the Reaction Attempts project, Andrew Lang noticed that there might be a quick synthetic route to praziquantel via a Ugi reaction. I researched it further and found a paper (Kim et al 1998) where Ugi product 1 was indeed converted to racemic praziquantel via the Pictet-Spegler cyclization.

Using Beilstein Crossfire the only synthesis of 1 I found involves a multi-step amidation strategy. But this compound should be accessible in one step from commercially available starting materials via a Ugi reaction (shown above). Since all the starting materials are liquids we have some flexibility with solvent choice. Khalid first tried it in methanol EXP258 a few weeks ago but did not get a precipitate. He was going to monitor it by NMR next to see if the problem was high solubility of the Ugi product or with the reaction itself.

It was therefore with great interest that I read Mat Todd's report this morning on The Synaptic Leap that a German patent had been issued on this Ugi strategy to praziquantel. (TSL didn't provide a means of leaving a comment so I edited the page - which made me the author of that post but actually Mat wrote it)

I have often mentioned during my talks that Open Notebook Science could be used not only in a defensive manner to claim academic priority - but also as an offensive tactic to block patent applications. A company attempting to prevent the commercial exploitation of rival inventions has a few options. Where applicable, it can buy up an existing patent pool with the intention of sitting on it. For new inventions, it can do research and try to file patents before their competitors. But this is a costly process and it may make more sense to simply publish the inventions to create disclosed prior art, thereby blocking patent applications of their competitors.

But - as I and many others have discussed - the current publication system is not optimally suited for the purpose of simply disclosing and communicating science. Not only is it generally slow but the traditional article format requires a narrative of some sort - rarely can single experiments be published. This means that much (if not most) of research done by an individual or group will never be disclosed.

For these reasons I think that keeping an easily discoverable Open Notebook for projects designed to block patent submission by competitors makes a lot of sense - both economically and from a workflow perspective. Since researchers already have to keep a lab notebook, making it public doesn't impose the added time that writing an article or patent will require.

In this specific example of praziquantel we were too late. But if we had recorded this experiment a few years ago it might have worked to block Domling's patent. Now, it isn't clear to me that EXP258 would have been enough to do that. The strategy to make praziquantel via a Ugi reaction was clearly stated but the experiment was not conclusive. However, since Domling reported that methanol worked I am sure that we would have had the "reduced to practice" evidence in the notebook shortly.

Above I used a company as an example of a party motivated to disclose inventions to protect their interests. In our case it would not be a company but rather the entire Open Science community. It is in our best interest to keep our scientific territory as unencumbered by patents as possible. Keeping Open Notebooks might be one of the simplest means of ensuring that.

Consider a humanitarian organization that might want to manufacture praziquantel. I haven't researched it but presumably the Domling patent was filed in a number of countries beside Germany. In order to consider using the Ugi strategy, the organization would now have to deal with the patent holder. This might be the factor that makes this route untenable. Patents have proven to be problematic for humanitarian aid - even in the simple case of providing food.

But all is not lost. In addition to offering a simple 2-step synthesis of praziqantel, the Ugi route offers an easy way to make large libraries of analogs. Optimally we would like to work with someone who has experience with docking praziquantel. It might be interesting to screen not only the praziquantel analogs but also the uncyclized Ugi products themselves. When we did this for malarial enoyl reductase inhibitors (D-EXP005) we found that we did not need to cyclize to obtain compounds predicted to bind. This ultimately led to active compounds.

1 June 2010: Have something to say about an article you’ve read on Chemistry World this week? Leave your comments below…

This week’s stories…

Basic research bill backed in US
US bill that boosts science funding passes on third attempt after Democrats employ unusual procedural tactic

Universities face hard years ahead
Funding cuts to universities across Europe as a result of the economic crisis will impact teaching and research quality for years to come, says report

Structural order gained over conducting polymer
Researchers have used copper as both catalyst and template to gain structural control over an important conducting polymer

Liquid marbles detect gases
Scientists use porous properties of liquid marbles to develop gas sensors

Instant insight: Cosmic dust as chemical factories
Daren Caruana and Katherine Holt discuss how electrochemistry could be the missing link to understanding chemistry in space

Big chemistry news this week was the announcement of the first synthetic cell, which could provide a basis for designing organisms from scratch.

Understandably the news has caused some controversy in the media, with sceptics concerned for the future of humanity and even research rivals worried that if the technology is patentable, other research groups will lose out on a piece of the pie.

The research could have enormous commercial value in the future for applications in biofuels and chemical synthesis through chemical biology and should be viewed as another step towards a greater understanding of science.

PHARMACEUTICALS

Cheap cancer drugs say Asda

So from creating synthetic cells to destroying cancerous ones…
In a world first supermarket Asda has announced that it will permanently sell privately prescribed cancer treatment drugs on a ‘not for profit’ basis in the UK, which could save patients thousands of pounds.

With a post code lottery on cancer funding dictating how much money is allocated to the treatment of each cancer patient, and the variation in cancer drugs available on the NHS depending on where you live, sufferers also have to deal with pharmacy mark-ups that can cripple patients’ finances.

Cancer affects nearly 300,000 people every year in the UK and the cost of treatment is too much for many sufferers. According to Asda, some privately prescribed cancer drugs are being sold with a 76 per cent mark-up in some high street stores.

This move will see prices of drugs like Iressa (gefitinib) – licensed to treat lung cancer – fall in Adsa stores to £2167.71 compared with other high street stores such as Superdrug that sell it for £3253.56.

Asda is urging patients to shop around when buying privately prescribed cancer drugs, claiming that 63 per cent of people were unaware that prices vary between pharmacies.

Asda has called for industry to follow its lead and end the high price mark-ups on cancer drugs and is working with suppliers to negotiate further discounts on trade prices of privately prescribed cancer drugs that it can then pass onto the customer.

Aspen to acquire Sigma Pharmaceuticals

African drug giant Aspen Pharmacare Holdings Ltd. has offered to buy leading Australian pharma firm Sigma Pharmaceuticals for A$1.49 billion (£850 million) in order to expand into Australia. The offer works out at A$0.60 per share and net debt of A$785 million.

The proposal is subject to conditions such as regulatory approval, and unanimous recommendation by the Sigma board – the company has confirmed that the approach has been made and is currently considering the offer.

Genzyme pays up

US firm Genzyme, the largest maker of genetic disease medicines, has agreed to pay $175 million (£121.5 million) in unlawful profits from the sale of products made at its Allston, Massachusetts, plant to the US federal government.

During an inspection in 2009, manufacturing quality at the Allston plant was found to be inadequate resulting in production delays, critical shortages of medically necessary products to consumers and drugs contaminated with metal, fibre, rubber and glass particles. These findings violated US Food and Drug Administration (FDA) regulations. Genzyme also suspended manufacturing of some of its products due to viral contamination in one of its bioreactors.

Genzyme has agreed to make improvements to its manufacturing processes at Allston, starting with an independent inspection of the plant that will recommend changes and result in an improvement plan subject to FDA approval. If the approved plan is not met, Genzyme will have to pay a substantial fine. In addition, Genzyme will have to move its vial filling operations to another plant or risk paying further disgorgement fines in the future.

INDUSTRY

Shin-Etsu’s new leadership

Japan’s most profitable chemical company, Shin-Etsu Chemical, has announced a change of leadership. Chihiro Kanagawa, former president, will become chairman, a position that has been vacant for over 15 years, and the former vice president, Shunzo Mori, will become president.

Kanagawa joined the firm in 1962, becoming president in 1990 and steering the company through some bold moves that have resulted in the company’s expansion over the years. Shunzo Mori is 74 and been at the company since 1963. He trained as a mechanical engineer and has worked his way up the company.

Shin-Etsu has extended profits and developed new areas of business, expanding its semiconductor silicon business by building on the strength of products such as silicone resins, synthetic quartz, rare earth magnets, cellulose derivatives and photoresists. PVC output has also increased and record earnings have been reported year on year.

The plans for the future include increasing sales in developing markets such as China and investing in improvements to accommodate environmental challenges.

Borouge and Linde Group get cracking

The Linde Group – a world leading gases and engineering company and Borouge – a leading provider of innovative plastic solutions – have signed a $1.1 billion contract confirming that Linde will build a 1.5 million tonnes per year (t/y) ethane cracker at Borouge’s production site in Ruwais, Abu Dhabi, in the UAE.

This deal comes hot on the heals of the inauguration of the world’s largest ethane cracker operated by Ras Laffan Olefins Co., that took place earlier this month.

The new cracker is the third of its kind to be built by Linde for Borouge in the last decade and will complement the existing crackers at the plant. Once the construction is complete, the Borouge site will be the largest ethane cracking complex in the world.

It signals a milestone in the growth of the company and is hoped to have a great impact on the automotive and advanced packaging markets in the Middle East and Asia.

SMEs pay less for chemicals

Small and medium enterprises (SMEs) in the chemicals sector are set to pay less in administrative charges following a decision by the European Commission. Small firms will pay less in fees to the European Chemicals Agency (ECHA) in connection with Classification, Labelling and Packaging Regulations (CLP) due to a reduction in levies.

The fees apply when a company asks for an alternative name for a substance or requests harmonised classification or labelling for substances.

Microenterprises will have a 90 per cent reduction in fees, small businesses will see a 60 per cent reduction, whilst medium size businesses will see a 30 per cent reduction and all companies that comply with CLP regulations will be able to work in their own language as the ECHA has now translated its guidance documents.

In addition to reduced fees SMEs will also be able to gain assistance with Registration, evaluation, authorisation and restriction of chemicals (Reach) regulations and CLP regulations.

And finally….

It seems that if you are a Chartered Chemical Engineer in the UK and Ireland, you can sit back and smile smugly. Results from the IChemE 2010 UK and Ireland Salary Survey reveal that the median salary for a Chartered Chemical Engineer is now £60,400 per year compared to £57,500 in 2008 even in this economic climate. Indeed a Chartered Chemical Engineer aged 30-39 will typically earn £8500 a year more than a non-chartered chemical engineer.

Is it time for a change in career we ask ourselves….

Mike Brown

Ever since the infamous US anthrax attacks of 2001, where envelopes containing anthrax spores were mailed to a number of media outlets and two US Senators, there has been a push to develop new ways of determining the severity of anthrax infections.

John Barr, of the US Centers for Disease Control and Prevention (CDC), has developed a new, more sensitive way of monitoring the level of infection in a victim. This is keenly important as the symptoms for anthrax infection start off looking much like a cold or the flu, but can then lead to a subject deteriorating rapidly – often leading to death, even after treatment. According to Barr some 40 per cent of the victims of the 2001 anthrax letters died.

The Bacillus anthracis bacterium produces two different t toxins, the oedema factor and the lethal factor. Barr has developed a way of detecting both of these using a liquid chromatography – mass spectrometry (LC-MS) approach that can provide earlier diagnosis than any other technique. This is particularly important as providing antibiotics at an early stage in the infection can increase the odds of survival.

His method, which uses an antibody purification step to extract the toxins, can detect the toxins at concentrations as low as 25pg/ml in about two hours. If the antibody extraction step is left for around 16 hours, that detection limit can fall as low as 5 pg/ml.

The progression of the infection tends to go through a brief remission, and the changes in lethal factor levels correlate with the clinical symptoms – and during remission other methods that rely on detecting the bacteria themselves often fail during this stage.

Barr believes his results should enable clinicians to predict the clinical outcome of an infection, which could prove immensely important as there have recently been a number of anthrax poisoning cases in Scotland, after heroin addicts injected themselves with anthrax-contaminated spores.

Matt Wilkinson

Fancy a smoke? No, it’s my last one and I need to get an urgent message to HQ…

Sadly, this line is yet to appear in a spy film, but thanks to George Whitesides and his group at Harvard University, US, it might one day. The group has had another stab at ‘infochemistry’ – using chemical means to convey a message or information without the need for an electrical power supply.

Avid readers of this blog will remember that in June of last year the group first mooted the idea of using ‘infofuses’ soaked in alkali metal solutions to transmit coloured light messages as they burned, and then the follow-up using a microfluidic device with a series of droplets passing by windows in the device to let light through – using intensity, colour and polarisation to encode more information than standard on-off digital signals.

This time, the team have developed their ‘infofuse’ idea. One of the major drawbacks of the original system was the fact that the fuses tended to go out if they were in contact with a surface, and also burned really fast – to keep a message like an SOS call or suchlike repeating for 24 hours would need 2.5km of fuse.

The answers sound simple and almost obvious – use a slower burning fuse and keep most of it lifted off the surface. But it’s never quite as easy as all that. Keeping the fuses off the surface was quite simple – crimping them into a tent-like shape held enough of the nitrocellulose far enough away from whatever surface the fuse was resting on to stop it sinking all the heat and putting out the flame.

But the timing problem required a more considered approach – simply using a slow burning fuse was no good – it would take hours to transmit the message, and most slow burning materials don’t burn hot enough to stimulate thermal emission of the alkali metal ions. What was needed was a combination – a slow burning ‘master’ fuse, with a series of fast ‘slave’ fuses sticking out of it. As the master fuse smoulders up to each slave fuse, it ignites and rapidly transmits its message.

This gives a compact system that can repeat a single, fast message over a long period, or transmit several different messages one after the other. The slow fuse is made from cotton soaked in sodium nitrate – similar to the ‘slow match’ used to ignite gunpowder charges in early matchlock firearms. However, the team showed that one could equally use a cigarette as the slow match – much less conspicuous if you’re an undercover agent…

Phillip Broadwith

Reference: C Kim, S W Thomas III and G M Whitesides, Angew. Chem. Int. Ed., 2010, DOI:
10.1002/anie.201001582

After sitting through a number of incredibly technical presentations today at ASMS I came across a fantastic poster presented by Shunyan Mo of the University of Illinois College of Pharmacy, US. Using an ultrafiltration LC-MS (liquid chromatography – mass spectrometry) assay, Mo and co-workers have shown that certain flavinoids found in cocoa selectively inhibit the cyclooxygenase-2 (Cox-2) enzyme and therefore could have anti-inflammatory effects.

As discussed in this Chemistry World article, Cox inhibitors such as naproxen play a vital role in the treatment of pain and inflammation, but they do have some side effects. To reduce these side effects, a number of pharmaceutical companies developed selective Cox-2 inhibitors, but unfortunately many of these were linked to an increased risk of blood clotting, heart attack and stroke. In 2004, those risks caused a huge embarrassment for Merck & Co., after it was forced to withdraw its blockbuster Cox-2 inhibitor Vioxx (rofecoxib) costing the company in the region of $4.75 billion (£3.3 billion) in legal settlements on top of the billions of dollars of lost sales.

But now, Mo has shown that eating chocolate might help reduce inflammation, and has identified using MS-MS experiments that two oxidation products of the abundant cocoa fatty acid, linoleic acid,  9-hydroxy-10,12-octadecadienoic acid (9-HODE) and 13-hydroxy-9,11-octadecadienoic acid (13-HODE) strongly and selectively inhibit Cox-2.

Perhaps unsurprisingly, the research was funded by US-confectionery company Hershey and the US National Institutes of Health (NIH).

So next time you need to reach for an anti-inflammatory, it might be worth reaching for a bar of chocolate instead – just don’t blame me if you put on a few pounds!

Matt Wilkinson