Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

MIT chemists find an easier way to synthesize new drug candidates

25.06.2010
New method could have a big impact on pharmaceutical business

Some drugs may be more effective the longer they last inside the body. To prevent such drugs from being broken down too rapidly, pharmaceutical manufacturers often attach a fluorine-containing structure called a trifluoromethyl group. However, the processes now used require harsh reaction conditions or only work in a small number of cases, limiting their usefulness for synthesizing new drug candidates for testing.

Now, MIT chemists have designed a new way to attach a trifluoromethyl group to certain compounds, which they believe could allow pharmaceutical companies to create and test new drugs much faster and potentially reduce the cost of drug discovery. The new synthesis, reported in the June 25 issue of Science, could have an immediate impact.

MIT Chemistry Professor Stephen Buchwald, who led the research team, says achieving the synthesis has been a long-standing challenge for chemists. "Some people said it couldn't be done, so that's a good reason to try," says Buchwald, the Camille Dreyfus Professor of Chemistry at MIT.

Eun Jin Cho, a postdoctoral associate in Buchwald's lab, is the lead author of the paper. Other authors are graduate student Todd Senecal, postdoctoral associates Tom Kinzel and Yong Zhang, and former postdoctoral associate Donald Watson, now an assistant professor of chemistry at the University of Delaware.

The trifluoromethyl group (abbreviated CF3) is a component of several commonly used drugs, including the antidepressant Prozac, arthritis medication Celebrex and Januvia, used to treat diabetes symptoms.

When foreign compounds such as drugs enter the body, they get sent to the liver, where they are broken down and shipped on to the kidneys for excretion. However, CF3 groups are hard for the body to break down because they contain three fluorine atoms. "Fluorine is not really a component of things we eat, so the body does not know what to do with it," says Kinzel.

CF3 groups are also a common component of agricultural chemicals such as pesticides. To add a CF3 group to organic (carbon-containing) molecules, chemists often use hydrogen fluoride under conditions that might produce undesired reactions among the many structural components found in complex molecules like pharmaceuticals or agrochemicals.

With the new reaction, the CF3 group can be added at a much later stage of the overall drug synthesis. The reaction can also be used with a broad range of starting materials, giving drug developers much more flexibility in designing new compounds.

Chemists have been trying to find a widely applicable catalytic method to attach CF3 to aryl compounds (compounds containing one or more six-carbon rings) for a couple of decades. Some have achieved different parts of the reaction, but none successfully put all the pieces together to arrive at a method that is applicable for a wide range of different aryl compounds. The major challenge has been finding a suitable catalyst (a molecule that speeds up a reaction) to transfer the CF3 entity from another source to the carbon ring.

CF3– (trifluoromethyl negative ion) tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes. The MIT team chose to use a catalyst built from palladium, a silvery-white metal commonly used in catalytic converters. The MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand (a molecule that binds to the metal to stabilize it and hasten the reaction) called BrettPhos, which they had previously developed for other purposes.

Coming up with a useful reaction required much testing of different combinations of palladium, ligand, CF3 source, temperature and other factors. "Everything had to match up," says Senecal.

During the reaction, a CF3 group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF3 unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 to 94 percent of the trifluoromethylated products.

In its current state, the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall costs because it streamlines the entire synthesis process. "For discovery chemistry, the price of the metal is much less important," says Kinzel.

All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method.

"This versatile new methodology is directly applicable to drug development," says John Schwab, a program director at the National Institute of Health's National Institute of General Medical Sciences, which partially funded the research. "This is a terrific example of how U.S. healthcare consumers are benefiting from their investment in NIH and in basic, biomedical research."

Source: "The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides." Eun Jin Cho, Todd D. Senecal, Tom Kinzel, Yong Zhang, Donald A. Watson, Stephen L. Buchwald. Science. 25 June, 2010.

Written by Anne Trafton, MIT News Office

Jennifer Hirsch | EurekAlert!
Further information:
http://www.mit.edu

Further reports about: CF3 CHEMISTRY Science TV catalytic converter drug discovery methyl group

More articles from Life Sciences:

nachricht Fingerprint' technique spots frog populations at risk from pollution
27.03.2017 | Lancaster University

nachricht Parallel computation provides deeper insight into brain function
27.03.2017 | Okinawa Institute of Science and Technology (OIST) Graduate University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Northern oceans pumped CO2 into the atmosphere

27.03.2017 | Earth Sciences

Fingerprint' technique spots frog populations at risk from pollution

27.03.2017 | Life Sciences

Big data approach to predict protein structure

27.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>