Scientists from The Scripps Research Institute have created a novel technique that for the first time will allow the efficient production of a molecular structure that is common to a vast array of natural molecules. This advance provides a means to explore the potential of this molecular substructure in the search for new therapies.
The study was published on May 23, 2010 in an advance online edition of the journal Nature Chemistry.
The structures in question, called "skipped polyenes," are shared by a large class of molecules that play a critical role in human health, including polyunsaturated fatty acids, which are vital to blood pressure regulation, inflammation, and immune response. The structures are also shared by a number of potent antibiotic, antifungal, and cytotoxic (toxic to living cells) compounds.
Simple and efficient methods for the preparation of skipped polyenes have generally been lacking, creating a significant barrier to exploring their potential as drugs. Currently, the production of molecules that contain simple variants of this substructure is quite labor intensive.
"Our study identifies a novel chemical reaction that will enable the accelerated production of this type of structural motif," said Associate Professor Glenn Micalizio, who authored the new study with a member of his Scripps Florida lab, Research Associate Todd K. Macklin. "This new reaction provides a means to explore the medicinal potential of molecules bearing complex skipped polyenes – something that we simply haven't been able to do until now."
Chemical Short Cuts
In essence, the new chemical method provides a means to replace long, step-by-step sequences of reactions that would have otherwise been required to prepare skipped polyenes. The new chemical process defines a fundamentally novel pathway (a new carbon-carbon bond forming process) to these complex structures that proceeds in just a fraction of the number of chemical steps previously required.
As such, the new method not only saves time, but greatly increases efficiency for the production of molecules that house the skipped polyene core. In chemistry, each of the steps (or reactions) used to prepare a complex structure typically proceeds with less than 100 percent efficiency, notes Micalizio—maybe 80 to 90 percent of the initial material can successfully be advanced to the next chemical step. As a result, the requirement of long sequences of reactions, where yields per step are compounded mathematically through the sequence, typically result in poor overall efficiency.
"If one can invent reactions that decrease the length of sequences required to prepare complex structures, great enhancements of efficiency can result," said Micalizio. "A central focus of our laboratory is designing new chemical reactions that do just that. Since 2005, we have been advancing a large class of chemical transformations that can be seen as 'chemical short cuts' – so that ultimately scientists can better explore the therapeutic potential of molecules inspired by the vast and diverse structures that we see in nature."
The new technique described in the Nature Chemistry paper proceeds by bond formation between two specific classes of molecules, vinylcyclopropanes and alkynes (or vinylsilanes), using a metal-promoted cross-coupling reaction to assemble the key structural motif.
"That initial metal-promoted coupling leads to a very unstable intermediate molecule," Micalizio said. "Actually, the chemical intermediate spontaneously rearranges to stabilize the structure, through a process that establishes all of the complex architecture of the skipped polyene product."
The research for the paper, "Convergent and Stereospecific Synthesis of Complex Skipped Polyenes and Polyunsaturated Fatty Acids," was supported by the American Cancer Society, the Arnold and Mabel Beckman Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.For information:
Keith McKeown | EurekAlert!
Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel
Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Business and Finance
22.11.2017 | Physics and Astronomy
22.11.2017 | Physics and Astronomy