Tag Archives: pharmaceutical

Researchers close in on making a natural malaria drug.

Westfall, PJ, DJ Pitera, JR Lenihan, D Eng, FX Woolard, R Regentin, T Horning, H Tsuruta, DJ Melis, A Owens, S Fickes, D Diola, KR Benjamin, JD Keasling, MD Leavell, DJ McPhee, NS Renninger, JD Newman and CJ Paddon. 2012. Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proceedings of the National Academy of Sciences http://dx.doi.org/10.1073/pnas.1110740109.

Synopsis by Jean-Philip Lumb

A new approach to making the natural malaria drug artemisinin will increase supply and avoid the chemical steps now used to extract the drug from plants. The drug is meant to replace medicines that no longer control the malaria parasite spread by mosquitoes.

An affordable treatment for malaria is closer thanks to a process using both biology and chemistry to make artemisinin – an effective drug currently extracted from plants.

The method bypasses plants as the source of the drug. Instead, modified yeast change sugar into an advanced chemical that can be converted into artemisinin. Skirting plants decreases the cost, increases supply and avoids chemical extractions. A team of industrial and academic researchers in Berkeley, Calif., developed the biochemical route to the drug.

The process provides an alternative to traditional extractive procedures and highlights the increasing use of biotechnology in greener drug manufacturing.

Globally, the mosquito-borne infectious disease claims nearly 1 million lives per year. Health organizations estimate that 300 – 500 million people are infected on an annual basis, a population based primarily of children in Africa and Asia.

New medicines are needed because the current drugs do not work as well as they once did and controlling mosquitoes with insecticides – such as DDT – can harm the environment and human health.

Artemisinin is a desirable substitute to the widely used chloroquine-based antimalarial drugs. The Plasmodium parasite that causes malaria has become resistant to these traditional drugs.

While faster acting and more effective, artemisinin is expensive and supplies are often limited. Artemisinin is currently extracted from plants. Unfortunately, the extraction makes large-scale production too costly for countries where the drug is needed most. The methods also employ volatile organic solvents that levy a heavy environmental toll.

To overcome the current limitations in supply, a consortium of industry and academic researchers in California developed a new strain of yeast that can convert glucose into an artemisinin precursor. Standard organic chemistry practices are used for the remaining steps of the drug’s synthesis.

The combined biotechnology/synthetic chemistry approach promises to be an effective alternative to the extraction techniques currently in use. The cost is estimated as low as 300 million cures at 50 cents a treatment. A recent press-release, issued on the Amyris website, announced a partnership between Amyris, The Institute for OneWorld Health and Sanofi-Aventis to make doses of artemisinin available later this year.

Read more science at Environmental Health News.

Safer anti-coagulants: Kicking out the pig.

Synopsis by Audrey Moores and Wendy Hessler, Feb 29, 2012


An approach combining chemistry and biology improves the process to make important anti-clotting drugs known as heparins. The heparin medicines prevent dangerous blood clots from forming in veins and are needed for surgery and kidney dialysis.

The technique provides easier access to safer drugs that are now either processed from pigs and cows or synthesized in a long, costly lab process. The novel method described in the journal Science provides a realistic alternative to livestock for heparins and is likely to drop the cost of such pharmaceuticals.

The process is not yet ready for large-scale commercial use, but its product yields are impressive.



Many pharmaceutical drugs are processed from plants or animals rather than made in a laboratory. While such a strategy may seem more natural, animal-sourced drugs are susceptible to contamination.

Heparins are a family of drugs used for more than 50 years to prevent blood clots in people. These complex molecules come from three main sources. They can be collected from pig intestines or cow lungs, synthesized in a laboratory or collected from animals and then modified in a lab.

The sizes and uses of the three types vary. The animal-sourced drug is the largest. It degrades rapidly in the body and is used for kidney dialysis and surgery. The chemically-altered animal heparin and the synthetic varieties are smaller, longer-lived molecules. Patients with venous thrombosis – the tendency for blood clots to form in veins – take these to prevent the clots.

Safety is an issue with the animal-sourced heparin, the cheapest and most accessible available. In 2007, drug contamination resulted in at least 200 deaths in the United States and raised concerns over the source of heparin.

GlaxoSmithKline synthesizes the smaller-sized heparin under the brand name Arixtra. Their process requires about 50 steps and yields very low amounts of material– around 0.1 percent. As a consequence, this molecule cannot currently replace animal-based heparins for all applications because of its high price.

The risk of contamination and current cost of synthesizing heparin is driving the quest to find a more efficient and cheaper way to make heparin drugs.


What did they do?

A team of chemists from the United States applied a strategy called chemoenzymatic synthesis to fabricate the heparin molecule. The method borrows from both chemistry and biology fields.It is an attractive way to synthesize heparin medicines. The drug contamination in 2007 occurred because the heparin collected from animals had an unusual chemical structure. People became allergic and hypersensitive. These side-effects would be avoided using a chemoenzymatic system because the series of chemical and enzymatic reactions needed to produce the drug are much better controlled than those in the animal gut where many proteins can alter the drug-to-be molecule.

In this study, the researchers mimicked the process animals use to make heparins. They chemically synthesized a starting material then added enzymes that lengthened and built the whole heparin molecule. In other words, they transferred what happens in the pig gut into a beaker. This approach is superior to collecting directly from an animal because the reactions are controlled.

To see if the manufactured drugs were effective, the researchers tested them in two different ways in the lab. First, they put them with two key proteins responsible for coagulating blood. Then, they injected rabbits with them and collected the animal blood. The interactions with the proteins alone in a culture and in the blood from the rabbit were measured and compared with the activity of the commercial heparin Arixtra.


What did they find?

The researchers discovered they could produce two heparin molecules with the impressive yield of 45 and 37 percent, in 10 and 12 steps respectively. They were able to make several milligrams of the product.

The two newly synthesized heparin molecules were similar in size to as the current Arixtra drug. They also proved as active as Arixtra. The efficacy of the interaction between the drugs and coagulating proteins were similar to Arixtra.

The same was true when the newly developed heparins were tested with rabbits. The drugs interacted with the same proteins as Arixtra.


What does it mean?

A more streamlined method to make anti-coagulant drugs may provide a realistic alternative to the animal-sourced pharmaceuticals, which are susceptible to contamination. The new process also produces more heparin product in shorter time and for less money than current synthetic preparations.

This means that the newly made heparins could be used in a wider range of applications than the current synthetic heparin Arixtra, because the reduced cost may open new markets.

This technique isolated 3.5 milligrams of heparin. The obvious next step will be to scale up this process to demonstrate that it is commercially feasible. It is estimated that 10 to 20 tons of heparin drugs are sold every year in the world.

The new drugs must also be tested and properly certified before they can be used commercially. However, the preliminary results of this research effort show that these two heparin molecules should be active anti-coagulant drugs with similar properties as the most popular synthetic version on the market today.

The type of synthesis – which merges chemistry techniques and biological enzyme actions – profiled here may be transferable to the manufacture of other drugs. Read more science at Environmental Health News.


Chemistry of Ginkgo

By Mana Sassanpour, 1/26/2011

After reading a book that mentioned the health benefits of ginkgo (leaf pictured right), I decided to see if there were any green chemistry related topics that involved this ancient and revered tree. The journal, Green Chemistry,  has an article about a more efficient means of extracting the useful components of ginkgo (Qingyong Lang and Chien M. Wai Green Chem., 2003, 5, 415-420). The researchers developed a greener method of pressurized water extraction which is a “a more effective, selective, economical and environmentally benign technique.”

However, the article did not make clear WHY they were bothering to finding greener ways to extract these compounds – what does ginkgo do? I could pay £34 GBP ($52.50) to find out why, but I thought doing my own investigation would be more fun and less costly.

My research took me in several directions, including the Encyclopedia of Medicinal Plants by Andrew Chevallier, Rebecca’s Natural Food Store in Charlottesville, VA, and to a friend, John Soong, who knows a little something about everything.

First, some history: the ginkgo tree dates back about 200 million years to the time of the dinosaurs.  Second, my friend John Soong explained that he had grown up eating ginkgo nuts in a rice porridge called congee (left). According to him, the philosophy behind eating ginkgo in Chinese cuisine is that “because the ginkgo tree has survived and lived for so long, if we eat it we will have the same longevity.”

There may be some science behind this belief: the active ingredients in ginkgo are purported to work together to produce a positive effect on the human body. The key ingredients are flavonoids, ginkgolide, and bilobalides. The Encyclopedia claims that ginkgo “improves circulation of blood to the head” which in turn leads to improved memory and is given to people with dementia. Ginkgo is also good for asthma and as an anti-inflammatory. Therefore it is not surprising that ginkgo has been noted as one of the bestselling medicines in Germany.

After my literature search, I drove to Rebecca’s Natural Food Store where one of the employees gave me an impromptu “Ginkgo 101” course. She explained that ginkgo is also a blood thinner and can help reduce the possibility of a stroke. In addition, she said it is “good for capillaries and oxygen uptake especially for those who always have cold hands and feet.” Hmmm: maybe I should start taking ginkgo?

Of course we are not qualified to make judgments or give advice on the medicinal value of ginkgo, but it seems like ginkgo is a very interesting plant. With such a wide array of potential health applications and valuable compounds, it makes sense to find more sustainable and cost effective methods of extraction.



1. Pressurized water extraction (PWE) of terpene trilactones from Ginkgo biloba leaves. Qingyong Lang and Chien M. Wai. Green Chem., 2003, 5, 415-420. DOI: 10.1039/B300496C

2. Encyclopedia of Medicinal Plants. By Andrew Chevallier – DK Pub. (1996) – Hardback – 336 pages – ISBN 0789410672


Warner Bacock Institute and Elm Street Ventures Launch ‘Occam Sciences’.

The Warner Babcock Institute for Green Chemistry and Elm Street Ventures Establish Occam Sciences to Develop and Commercialize Novel Forms of Existing Medicines
New Haven, CT and Wilmington, MA – The Warner Babcock Institute for Green Chemistry (WBI) and Elm Street Ventures (ESV) have announced today the formation of Occam Sciences in New Haven, CT to develop new forms of existing drugs with optimized bioavailabilty, including oral forms of medicines previously administrable only in a parenteral manner.
”We are delighted to join forces with WBI to develop new forms of already proven drugs that will offer important clinical benefits to patients”, said Rob Bettigole, Managing Partner of ESV. “Occam promises to be one of those rare start-ups that offers multiple bottom lines: better health for patients, improved environmental profile, profits for investors, and jobs for Connecticut and Massachusetts.”
WBI was cofounded in 2007 by Dr. John Warner, one of the founders of the field of Green Chemistry and co-author of Green Chemistry: Theory and Practice, a book that has revolutionized conventional wisdom across all industries touched by the chemical enterprise. Occam Sciences’ development efforts will utilize WBI’s proprietary non-covalent derivatization (NCD) technology to dial in selected physical properties for target drugs.
“We are pleased to have this opportunity to extend WBI’s NCD technology – already successfully commercialized in other industries – into the pharma realm”, said Joe Pont, CEO of WBI. “Our partnership with Elm Street Ventures is ideal given ESV’s deep network in both academic and industrial medical circles.”
Elm Street Ventures is a seed and early stage venture capital fund based in New Haven, Connecticut. An important part of ESV’s efforts is focused on creating and initially operating life sciences companies founded on intellectual property developed at Yale University and other research institutions in the New York City – New England region. Occam Sciences is ESV’s twelfth company. By providing management expertise and early stage capital, ESV catalyzes new company formation, working closely with scientists, engineers, and entrepreneurs to build significant technology companies. For more information, visit www.elmvc.com.
The Warner Babcock Institute for Green Chemistry provides innovation solutions and services across all markets and industries, from idea creation through commercial product optimization. WBI is committed to its clients, to society, and to the environment to create technologies and processes that are functional, cost-effective, and environmentally benign. For more information, please visit www.warnerbabcock.com.


Greening up drug production includes changing chemists, too.

Henderson,RK, J-G Concepcion, DJC Constable, SR Alston, GGA Inglis,G Fisher, J Sherwood, SP Binks and AD Curzons. 2011. Expanding GSK’s solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry. Green Chemistry http://dx.doi.org/10.1039/c0gc00918k.

Synopsis by Wim Thielemans
May 27, 2011

The large drug company GlaxoSmithKline (GSK) is reducing the use of problematic solvents in drug production in a unique way. They are changing the behavior of medicinal chemists – the researchers who develop new drugs.

An article in the journal Green Chemistry describes the company’s efforts to target the chemists by updating a popular green solvent guide and having the solvents easily available. The researchers’ choice of solvents is usually copied for industrial production of the drug. A change to a less harmful solvent has an enormous impact in creating a cleaner and safer pharmaceutical industry.

Organic chlorinated solvents are used in large quantities to produce pharmaceutical drugs. To produce 1 kilogram (kg) (2.2 pounds) of active drug, an average of 46 kg (100 pounds) of raw materials are used. Of these raw materials, an average 56 percent – or 26 kg (47 pounds) – are solvents.

Historically, medicinal chemists had a single focus: to develop new drug molecules in the shortest time possible. Solvent choice was purely based on familiarity with the chemical’s properties. Time to explore other, cleaner, solvents was not available as it slowed down new developments. The current focus on sustainability and safety is changing this single focus approach.

GSK’s approach is based on a solvent selection guide published in 1998. The guide ranks common solvents based on their environmental, health and safety issues. A 2003 update includes life cycle assessments – the environmental effects from production and disposal.

This latest edition extends the list of solvents to 110 from 47. It also provides more details in the assessments and presents a quick and comprehensive selection reference guide to steer scientists away from the most problematic solvents.

The complete solvent selection guide scores each solvent  from 1 to 10 – one is bad, 10 is good – for eight categories. The categories include: waste treatment after use, environmental impact, human exposure and health effects, flammability, stability, life cycle impact from production, legislative limitations on its use and melting and boiling point.

Color coding makes it easier to understand. The combination of all data on one poster allows direct comparison. In addition, an electronic version includes links to documents with further information.

The guide alone was not enough to boost the use of greener solvents, so the company combined it with other methods to promote them. The greener solvents were readily available in the stockroom, the solvent selection guides were posted, and the benefits of less hazardous solvents were highlighted.

Chemists at GSK choose the greener solvent if they were aware of it. For example, the greener solvent 2-methyltetrahydrofuran is replacing other more problematic solvents. It was used in 16 percent of studies in 2007-2009 instead of 3.5 percent in 2005-2006.

The authors conclude that real changes can be made by improving  availability of information, guidance and the actual solvents. The solvent selection guide described is a powerful tool. It is publically available, so it can be used by the whole scientific community and competing companies.

Even though reducing overall use of solvents should be the ultimate aim, this approach constitutes an important step in the right direction to a truly sustainable chemical and pharmaceutical industry, according to the study’s researchers.