Professor's research may benefit pharmaceutical advances

by Neil Thomas

University of Illinois at Chicago researchers, working in cooperation with the University of Delaware X-ray crystallographic center, have successfully synthesized and determined the structure of two rare forms of carbohydrate molecules that may prove useful in biological and pharmacological research and development.

The syntheses were reported in the June 20 issue of the Journal of the American Chemical Society, chemistry's highest ranking journal. The work is also highlighted in the Science Concentrates section of the June 25 Chemical and Engineering News.

The UIC team, led by David Crich, synthesized two different beta-mannans-oligosaccharides, or polymeric carbohydrates, containing only the beta-mannose type linkage. The researchers chose to synthesize the beta-mannans, in part, because of the challenge: the beta-mannoside linkage was one of the most difficult to prepare in carbohydrate chemistry until the problem was solved in 1997 by Crich and a graduate student.

"We have now moved on to synthesize oligomeric beta-mannosides," said Crich. "This is the first synthesis of beta-mannans, the oligosaccharides derived from beta mannose, in a controlled manner. If not the 'Everest' of carbohydrate chemistry, it's certainly K2."

All of the actual synthetic work on the molecules was done by two of Crich's graduate students and research collaborators included UIC chemistry professor and department head Donald Wink, along with Arnold Rheingold, UD professor of chemistry and biochemistry, and UD graduate student Roger Sommer, who carried out supporting X-ray crystallography studies.

"The UIC chemists understood that the compound they were working with was related to sugar in its broader chemical composition and behavior but they lacked detailed information about the exact structure of the molecule," Rheingold said. "Since function (in this case linked to the manifestation of a disease) is determined by structure, a detailed knowledge of the disease was not possible until they had knowledge of the full three-dimensional molecular architecture."

Rheingold said the UIC researchers sent the center a very small crystal of the compound they isolated and the UD crystallographers determined the arrangement of atoms in the crystal using X-ray diffraction methods.

"The very small size of the crystal, perhaps only 1/100th the size of what was the minimum needed for an X-ray study a few years ago, required the use of our new super-sensitive X-ray detector just acquired with funds from the National Science Foundation," Rheingold said. "To get the full structure, we needed to measure the intensities of over 40,000 reflections from the crystal.

"In the end, it proved to be one of largest undertakings in the history of this lab, which has determined the structures of about 6,000 different compounds in the last 20 years for hundreds of collaborators worldwide."

The two beta-mannans Crich's team selected are linked to disease states. One is the oligosaccharide found on Leptospira biflexa, a bacteria that causes leptospirosis, a painful and sometimes fatal disease common in subtropical Africa. The other is Candida albicans, a yeastlike fungus that causes candidiasis, or moniliasis, which affects the skin and sometimes the respiratory system.

Candida albicans "is an important clinical pathogen with an interesting activity in that it induces tumor necrosis factor-alpha, or TNF-alpha, which has implications in cancer chemotherapy," Crich said.

The work was supported by a grant from the U.S. Public Health Service, National Institutes of General Medical Science.