Scientists find easier, cheaper way to make a sought-after chemical modification to drugs

Scientists at The Scripps Research Institute have devised a much easier technique for performing a chemical modification used widely in the synthesis of drugs and other products.

Known as "trifluoromethylation," the modification adds a CF3 molecule to the original compound, often making it more stable—and, for a drug, keeping it in the body longer. With the new technique, chemists can perform this feat using a relatively simple, safe, room-temperature procedure and can even select the site of the modification on the target compound.

"I've been presenting this methodology at several pharma companies, and there's a lot of interest—so much so that their chemists are starting to use it," said Scripps Research Professor Phil S. Baran, senior author of the new study, scheduled for publication the week of August 15, 2011, in an advance online edition of the Proceedings of the National Academy of Sciences.

Standard procedures for trifluoromethylation involve gases and associated hardware, high heat, metal catalysts, and oxidants. "The procedures are often prohibitively complicated, and medicinal chemists often don't have the time or the resources to get into it," said Baran.

Inspired by frequent consulting visits to pharmaceutical companies, Baran and his lab began to look for simpler ways to perform trifluoromethylation. After running more than 500 different reaction setups on a test compound, they found just one that delivered significant quantities of the desired reaction product. It was a simple setup that used a reagent known as sodium trifluoromethanesulfinate, an inexpensive chemical that is stable at room temperature.

Chemists had long believed that this reagent was unsuitable for trifluoromethylating a broad class of molecules frequently found in drug compounds, and also that the reagent required the use of catalyzing metal salts. But in this initial screening, the reagent, known as Langlois's reagent for its discoverer, the French chemist Bernard R. Langlois, seemed to work even without such constraints.

Baran and his team began collaborating with fellow Scripps Research chemistry Professor Donna Blackmond and members of her laboratory to study how Langlois's reagent works and to optimize its use, including the selection of trifluoromethylation sites on target compounds using certain solvents. With the optimized technique, they showed that they could directly and easily trifluoromethylate a variety of test compounds, including the natural malaria drug quinine and the synthetic anti-smoking drug varenicline (Chantix).

"The collaboration with Donna Blackmond and her lab was crucial in enabling us to improve the procedure and to understand why certain modifications led to those improvements," said Baran.

The new technique in principle makes it more feasible for pharmaceutical companies to modify and improve specific drug compounds of interest. It also means that these companies can expand the existing compound libraries they use for drug-discovery screening by making trifluoromethylated versions of these compounds quickly and easily.

"In one instance, a chemist at Pfizer told me that the trifluoromethylated compound we made in one step with our technique would have taken at least eight steps using standard techniques," said Baran.

The Baran and Blackmond labs are now working on new reagents that may be used in this reaction and ways to enable fine control of trifluoromethylation sites. "The interplay of the two labs at the nexus of synthesis and mechanistic analysis is driving this project forward in new and exciting directions," Baran said.

More information: "Innate C-H Trifluoromethylation of Heterocycles," Proceedings of the National Academy of Sciences.

Provided by The Scripps Research Institute (news : web)

New polymeric material brings companies one step closer to cheaper plastic solar cells and electronics

A single polymer that can be used in both new age plastic electronics as well as plastic solar cells could spell greater cost-savings and open up new design options for electronic and solar cell companies. A*STAR’s IMRE has developed a new polymer that not only produces a high charge mobility of 0.2 cm2/V.s, which is the same value achieved by commercially available semiconducting materials but also has a high solar power conversion efficiency of 6.3%. This makes IMRE’s polymer one of the few that has both these properties. In addition to this, polymers of the same class as IMRE’s, which are those that use thiophene and benzothiadiazole as the building blocks, could only achieve 2.2% power conversion.

“Current polymers are usually good in one aspect or another, either as a good conductor for use in electronics or endowed with high power conversion efficiency - but not both”, said IMRE Senior Scientist, Dr. Chen Zhi Kuan, the principal researcher working on the polymers. “IMRE’s polymer functions not only as a good material to make electronic components, the same material can be used to convert sunlight to electricity efficiently”. The polymer can also be easily applied in roll-to-roll printing techniques which is similar to how newspapers are currently printed making it possible to manufacture large area-scale printed electronics and organic solar cells quickly and cheaply.

With IMRE’s polymer, manufacturers could save cost using just a single bulk resource for making both printed electronics and organic solar cells. The material could also possibly be used in designing new devices where both power harnessing and electronics are needed in a single component. An example of this would be chemical sensors based on organic thin-film transistors and powered by organic solar cells.

“This breakthrough will help speed up the development of plastic electronics and organic solar cells, and make them more readily available in the marketplace,” said Prof Andy Hor, Executive Director of IMRE.

 

IMRE?s polymer has both high charge mobility and high power conversion efficiency in a single material as opposed to most polymers that have either one or the other, not both - A transmission electron microscopy image of the IMRE polymer, PC71BM film, showing phase separation between the polymer fibres (light) and PC71BM (dark). Credit: Agency for Science, Technology and Research (A*STAR)

Printed electronics often rely on organic materials like polymers that can be easily processed and manufactured as opposed to traditional electronics (or metal electronics) which rely on inorganics such as copper or silicon. The polymers can be made into thinner, lighter and cost-effective electronic components and organic solar cells.

The IMRE team is developing other organic materials-based polymers that can be scaled up to production and integrated easily into organic electronics. These materials can be used to make energy harvesting and low-power consumption devices like low-cost organic solar cells, new flexible display devices, next generation smart labels and RFID tags.

The research and results were recently published in Advanced Materials.

Provided by Agency for Science, Technology and Research (A*STAR)

Candle flames contain millions of tiny diamonds

 The flickering flame of a candle has generated comparisons with the twinkling sparkle of diamonds for centuries, but new research has discovered the likeness owes more to science than the dreams of poets.

Professor Wuzong Zhou, Professor of Chemistry at the University of St Andrews has discovered tiny diamond particles exist in candle flames.

His research has made a scientific leap towards solving a mystery which has befuddled people for thousands of years.

Since the first candle was invented in ancient China more than 2,000 years ago, many have longed to know what hidden secrets its flames contained.

Dr Zhou’s investigation revealed around 1.5 million diamond nanoparticles are created every second in a candle flame as it burns.

The leading academic revealed he uncovered the secret ingredient after a challenge from a fellow scientist in combustion.

Dr Zhou said: “A colleague at another university said to me: “Of course no-one knows what a candle flame is actually made of.

“I told him I believed science could explain everything eventually, so I decided to find out.”

Using a new sampling technique, assisted by his student Mr Zixue Su, he invented himself, he was able to remove particles from the centre of the flame – something never successfully achieved before – and found to his surprise that a candle flame contains all four known forms of carbon.

Dr Zhou said: "This was a surprise because each form is usually created under different conditions."

At the bottom of the flame, it was already known that hydro-carbon molecules existed which were converted into carbon dioxide by the top of the flame.

But the process in between remained a mystery.

Now both diamond nanoparticles and fullerenic particles have been discovered in the centre of the flame, along with graphitic and amorphous carbon.

The discovery could lead to future research into how diamonds, a key substance in industry, could be created more cheaply, and in a more environmentally friendly way.

Dr Zhou added: “Unfortunately the diamond particles are burned away in the process, and converted into carbon dioxide, but this will change the way we view a candle flame forever.”

The famous scientist Michael Faraday in his celebrated 19th century lectures on “The Chemical History of a Candle” said in an 1860 address to the light: “You have the glittering beauty of gold and silver, and the still higher lustre of jewels, like the ruby and diamond; but none of these rival the brilliancy and beauty of flame. What diamond can shine like flame?”

Rosey Barnet, Artistic Director of one of Scotland’s biggest candle manufacturers, Shearer Candles, described the finding as "exciting".

She said: "We were thrilled to hear about the discovery that diamond particles exist in a candle flame.

"Although currently there is no way of extracting these particles, it is still an exciting find and one that could change the way people view candles. The research at St Andrews University will be of interest to the entire candle making industry. We always knew candles added sparkle to a room but now scientific research has provided us with more insight into why.”

Provided by University of St Andrews

Utah researcher helps artist make bulletproof skin

engineered spider silk can be used to help surgeons heal large wounds and create artificial tendons and ligaments.

Researcher Randy Lewis and his collaborators gained worldwide attention recently when they found a commercially viable way to manufacture silk fibers using goats and silkworms that had spider genes inserted into their makeup.

Spider silk is one of the strongest fibers known and five times stronger than steel. Lewis' fibers are not that strong but much stronger than silk spun by ordinary worms.

With Lewis' help, Dutch artist Jalila Essaidi conducted an experiment weaving a lattice of human skin cells and silk that was capable of stopping bullets fired at reduced speeds.

"Randy and I were moved by the same drive I think, curiosity about the outcome of the project," Essaidi said in an email interview. "Both the artist and scientist are inherently curious beings."

Lewis thought the project was a bit off the wall at first, Essaidi acknowledged.

"But in the end, what curious person can say no to a project like this?" she said.

Essaidi, who used a European genetics-in-art grant to fund her project at the Designers & Artists 4 Genomics Awards, initially wanted to use Lewis' spider silk from goats to capitalize on the "grotesque factor" of the mammal-spider combination.

But Lewis didn't yet have enough of the spider goat silk to send hundreds of yards to Essaidi. So he sent her spools of silk from silkworms he had genetically engineered in a fashion similar to the goats.

Essaidi initially intended to fire .22 caliber bullets at the "skin" stretched in a frame. But she decided to place the "skin" on a special gelatin block used at the Netherlands Forensic Institute.

Using a high-speed camera, she showed a bullet fired at a reduced speed piercing the skin woven with an ordinary worm's silk But when tested with Lewis' genetically engineered worm's silk grafted between the epidermis and dermis, the skin didn't break. Neither was able to repel a bullet fired at normal speed from a .22 caliber rifle.

"We were more than a little surprised that the final skin kept the bullet from going in there," Lewis said of the tests at reduced speed. "It still ended up 2 inches into the torso, so it would not have saved your life. But without a doubt the most exciting part for us is the fact that they were able to recreate the skin on top of our fibers. It's something we haven't done. Nobody has worked in that area."

Essaidi was intrigued by the concept of spider silk as armor, and wanted to show that safety in its broadest sense is a relative concept, hence bulletproof.

"If human skin would be able to produce this thread, would we be protected from bullets?" she wondered on her blog. "I want to explore the social, political, ethical and cultural issues surrounding safety in a world with access to new biotechnologies."

She said it is legend that Achilles was invulnerable in all of his body except for his heel.

"Will we in the near future due to biotechnology no longer need to descend from a godly bloodline in order to have traits like invulnerability?" she asked.

Lewis downplayed the potential bulletproof applications of his research.

"I certainly would not discount that, but I don't see that as a tremendous application at the moment," he said.

He said bulletproof vests already exist. But being able to grow cells and use the material to replace large amounts of human skin could be significant for surgeons trying to cover large wounds, or treat people with severe burns.

He said the material's strength and elasticity would enable doctors to cover large areas without worrying about it ripping out - a big advantage over small skin grafts.

Lewis couldn't give a time frame for such a use because it would require FDA approval. But he hoped to do some animal testing within two years, and noted spider silk already has proven very compatible with the human body.

The next step is to generate more material to test what cells will grow on it - made easier with the "transgenic" silk worms and milk from goat spiders.

The real stuff is still the holy grail for fibers and textiles but not the easiest to come by as evidenced by an 11-by-4 foot tapestry unveiled two years ago at the New York Museum of Natural History that took millions of spiders to complete.

"We know some skin cells will grow (on our fibers), but can we get cells that make ligaments and tendons grow," Lewis said.

He said it may be easier to use the genetically engineered silk to make materials better than actual ligaments or tendons.

Essaidi, meanwhile, said she has plenty of wild ideas but wants to transplant the bulletproof skin.

She said Geert Verbeke, director of Verbeke Foundation in Belgium, the biggest Eco/BioArt museum, wants to wear the skin "as an ode to BioArt."

Back at Utah State's bio-manufacturing facility in Logan, Utah, Lewis just started breeding for the next round of milking in January. He has about three dozen of the genetically engineered goats. He extracts proteins from the special milk then spins them in a way that replicates the spider's method, resulting in a strong, light-weight fiber.

"Nothing is as strong as the natural fiber, yet," Lewis said of spider silk. "But we are working on solving that problem."