Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps research team achieves critical step to opening elusive class of compounds to drug discovery

07.11.2011
Taxanes are a family of compounds that includes one of the most important cancer drugs ever discovered, Taxol®, among other cancer treatments. But the difficulty producing these complex molecules in the lab has hampered or blocked exploration of the family for further drug leads.

Now, a group of Scripps Research Institute scientists has successfully achieved a major step toward the goal of synthetically producing Taxol® and other complex taxanes on a quest to harness chemical reactions that could enable research on previously unavailable potential drugs.

The project, led by Scripps Research chemist Phil Baran, is described November 6, 2011 in an advance, online issue of the journal Nature Chemistry.

Taxol®, the trade name for a chemical called paclitaxel first discovered in 1967 in the bark of a yew tree, is a highly successful drug used to treat ovarian, breast, lung, liver, and other cancer types. No less than seven different research groups have designed several ways to produce Taxol® synthetically, beginning in the 1990s with a team led by K.C. Nicolaou, chair of the Scripps Research Department of Chemistry.

While each synthesis was a significant accomplishment, each has also been exceedingly complex and inefficient. Using all these methods collectively, researchers have produced less than 30 milligrams of synthetic Taxol®. Producing other chemicals from the same promising taxanes chemical group is nearly as challenging, vastly limiting access to them for research.

Building Ferraris

Finding an efficient way to produce Taxol® in sizable quantity in the laboratory remains one of the most sought-after and elusive goals in organic chemistry. If accomplished, it would open the door to producing countless other taxanes that are not accessible from nature. Past methods were devised using conventional schemes where researchers plot a linear path of increasingly complex molecules leading to a target compound. Creating each increasingly complex molecule along that line is an inefficient process that often requires numerous extra steps to prevent unwanted reactions or to correct other chemical complications. "It's like trying to convert a Toyota Corolla into a Ferrari instead of just building a Ferrari," said Baran.

To build the Ferrari, Baran and his team are taking a different route. In 2009, the researchers showed that by using an unconventional scheme they could produce a simpler relative of Taxol® called eudesmane. They analyzed this target and then created what Baran calls a retrosynthesis pyramid. This is a diagram with the target compound at the top and lower levels filled with molecules that could theoretically be modified to reach the level above them. Such a pyramid reveals not a set linear path, but a variety of path options open to chemical exploration.

With taxanes and related compounds there are two main phases in production, the cyclase phase and oxidase phase. Working up the bottom half of the pyramid involves mostly well-understood chemistry. During this cyclase phase, researchers construct a chemical scaffolding that Baran likens to a Christmas tree to which ornaments must then be attached. The ornaments are primarily reactive oxygen molecules and this "decoration," or oxidation, phase is the most challenging.

The eudesmane synthesis was something like decorating the Charlie Brown Christmas tree, while a completed Taxol® production could be compared to the lighting of the famous multi-story Rockefeller Center tree.

In the new paper, Baran's group reports erecting that Rockefeller tree and adding the first few ornaments -- a molecule called taxadiene. "It's a Herculean task," said Baran of Taxol® synthesis, "What we're doing here is merely part one."

A conventional taxadiene synthesis is inefficient and involves 26 steps to produce. The Baran group's method involves just 10 steps to produce many times what has been previously synthesized -- more than sufficient for planned research to find a way to efficiently produce Taxol®.

Innovation Leads to Access

The taxadiene synthesis is more than just a midway stop on the way to Taxol®. The researchers chose this molecule intentionally because, like a Christmas tree that can be decorated in any number of ways, this molecule can be modified to create a wide range of taxanes of varying complexities.

This is key, because at its heart the research isn't only about finding a better way to produce Taxol®, even though the group is working toward that goal. The current commercial Taxol® production method, which involves culturing cells from the yew tree, is more economical than any new synthesis is likely to be.

Instead, Baran and his team are aiming to understand the processes used in nature to produce the compound, which are many times more efficient than those used by scientists to date. "It's my opinion that when there's a huge discrepancy between the efficiency of nature and humans, in the space between, there's innovation."

More specifically, Baran believes that while developing an efficient synthesis for Taxol®, they will gain a fundamentally improved understanding of the chemistry involved and develop more widely applicable techniques. Such innovation could allow production of a whole range of taxanes currently inaccessible for drug discovery research either because the quantities researchers can produce are vanishingly small, or because they can't produce them at all. Control of the taxane oxidation process therefore offers the potential for discovering new and important drugs, perhaps even one or more that is better at fighting specific cancers than Taxol®.

Establishing the remaining steps between taxadiene and Taxol® or other more complex taxanes remains a challenging task that Baran estimates will take years. "Nature has a choreography in the way she decorates the tree," he said. "It's a precise dance she has worked out over millennia. We have to figure out a way to bring that efficiency to the laboratory setting."

This research was supported by the National Institutes of Health, the Fulbright Scholar Program, the National Sciences and Engineering Research Council of Canada, and Bristol-Myers Squibb.

In addition to Baran, authors on the paper, entitled, "Scalable, enantioselective taxane total synthesis," were co-first authors Abraham Mendoza and Yoshihiro Ishihara, both of Scripps Research.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>