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Biological Chemistry

Despite Its Expanded Mission, Riken Continues Its Rich History of Chemical Research

Rooted in Chemistry

by Amanda Yarnell
December 5, 2005 | A version of this story appeared in Volume 83, Issue 49

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Credit: Courtesy of Shigenori Fujikawa
Credit: Courtesy of Shigenori Fujikawa

RIKEN, a sprawling comprehensive research institute spanning the life and physical sciences, today bears little resemblance to when it was founded in 1917 as the Institute of Physical & Chemical Research. Yet it has not forgotten its roots; the institute is still home to a remarkable range of chemical research.

As it has in the past, RIKEN shines in the field of catalysis. For instance, Zhaomin Hou is developing organometallic catalysts for more efficient chemical synthesis. His lanthanide metal hydrides have proven useful for, among other things, the copolymerization of ethylene and norbornene (Angew. Chem. Int. Ed. 2005, 44, 962). Such copolymers may find use in optical lenses and compact discs.

Mikiko Sodeoka is also developing catalysts for organic synthesis. She recently reported a chiral palladium catalyst for the enantioselective fluorination of oxindoles. She's demonstrated the reaction's utility by synthesizing a Bristol-Myers Squibb molecule now in Phase III clinical trials for the treatment of stroke (J. Am. Chem. Soc. 2005, 127, 10164).

As RIKEN has expanded to include life sciences, many of its chemists have begun to focus on using chemical synthesis to answer biological questions. Sodeoka has used her palladium catalysts to make small molecules to probe the mechanism of a type of cell death known as necrosis. In a similar manner, Yukishige Ito's lab is chemically synthesizing complex mannose-containing sugars to probe the role these sugars play in the folding, trafficking, and degradation of proteins. Elsewhere at RIKEN, Yoshihiro Ito is using his knowledge of polymer synthesis to create polymer supports for culturing stem cells.

CHIRAL SUCCESS
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Sodeoka has demonstrated the utility of her chiral palladium catalyst by installing the fluorine group in the synthetic target shown, a molecule under investigation for the treatment of stroke.
Sodeoka has demonstrated the utility of her chiral palladium catalyst by installing the fluorine group in the synthetic target shown, a molecule under investigation for the treatment of stroke.

Historically, RIKEN has a strong tradition of natural product research. That activity now has evolved to tracking the molecular targets of natural products. For example, Hiroyuki Osada's team is fabricating small-molecule microarrays that can be used to probe the protein targets of small molecules. These microarrays can also be used to elucidate structure-activity relationships for a given protein target, he notes.

And Minoru Yoshida's lab is identifying the molecular targets of small molecules. His team recently reported that the microbial metabolites trichostatin A and trapoxin, as well as a reduced form of FK228, a potent anticancer agent now in Phase II clinical trials, act by inhibiting histone deacetylases. This class of enzymes has become a hot drug target, and Yoshida's lab is now making molecules that might block the action of specific histone deacetylases.

The institute also continues its long tradition of world-class accelerator and synchrotron science. In July 2004, for example, Kosuke Morita and his colleagues at RIKEN's heavy ion linear accelerator facility synthesized a few atoms of element 113 by exposing a 209Bi target to a beam of 70Zn ions and detecting the resulting 278[113]. They confirmed this synthesis earlier this year. Although a joint Russian-American team independently synthesized element 113 around the same time (C&EN, Feb. 9, 2004, page 7), Morita says there is still a good chance RIKEN will be awarded naming rights to the new element. Japonium and Rikenium are at the top of his list.

At RIKEN's 8-GeV synchrotron facility in Harima, a fully automatic protein crystallization robot and a robotic system for high-throughput X-ray analysis and data collection promises to advance the institute's push in structural genomics. Harima is also building a free-electron laser that will enable researchers to capture protein structures without crystals, watch the dynamics of molecular dissociations, and observe structure below the surface of materials. The laser is expected to be up and running in 2010, joining ones planned in the U.S. and Europe.

RIKEN's chemical tradition is being carried on by those outside of chemistry, too. Neuroscientists Takaoki Kasahara and Tadafumi Kato of RIKEN's Brain Science Institute previously showed that pyrroloquinoline quinine (PQQ) plays a critical biochemical role in lysine breakdown. Because mammals can't synthesize PQQ, Kasahara and Kato concluded that PQQ qualifies as a vitamin. More recently, Kasahara has synthesized radiolabeled PQQ and developed a spectrometric method to detect it in human tissue and food.

In addition, neuroscientist Takaomi C. Saido has developed a chemical probe that may prove useful in the early diagnosis of Alzheimer's patients. Currently, doctors can diagnose the disease only when patients begin to show memory loss and other symptoms. Saido recently showed that his fluorinated benzylstyrene probe can be used for magnetic resonance imaging of tiny clumps of amyloid protein in the brains of mice years before they develop the symptoms typical of Alzheimer's (Nat. Neurosci. 2005, 8, 527). If these results can be extended to human patients, we might be able to develop treatments that push off the disease, Saido says.

MORE ON THIS STORY

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Despite Its Expanded Mission, RIKEN Continues Its Rich History Of Chemical Research.

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RIKEN's five institutes are located on Honshu, Japan's largest island.

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