CHAPEL HILL - After 12 years work, chemists at the University of North Carolina at Chapel Hill have succeeded in completely synthesizing ginkgolide B, a complex molecule produced naturally by what may be the world's oldest living plant.
"Ginkgolide B is isolated from the ginko tree, which Charles Darwin called a living fossil," said Dr. Michael T. Crimmins, professor of chemistry at UNC-CH. "The extracts have been used for thousands of years as herbal medicines and have been attracting a lot of attention recently. The complexity of the molecule caused us to change our approach several times, and that's why the synthesis required so much time."
The compound is one of the active ingredients in such commercial products as Ginkoba, touted by its manufacturer as being able to boost alertness and other mental functions, Crimmins said. The natural product currently is being tested in clinical trials for treating dementia, multiple sclerosis and other illnesses.
A report on the new work should appear in a chemistry journal in the fall, probably the Journal of the American Chemical Society, he said.
Female ginkgo trees, which date back about 250 million years, bear sticky, foul-smelling fruit, Crimmins said. Both male and female trees produce fan-shaped leaves with parallel veins unlike any other plant.
"Ginkgo extract has been used to treat coughs, allergic inflammations, circulatory disorders and other conditions in Asian cultures such as India and China," Crimmins said. "Recent, still-early studies have shown it apparently does have some effect in delaying the onset of Alzheimer's disease."
Ginkgolide B, which scientists call a platelet-activating factor antagonist, is the most active component of the extract in terms of helping treat asthma and other allergic responses, he said. Five or more ginkgolide-type molecules occur, but ginkgolide B also is one of the most complicated.
The UNC-CH chemists began their synthesis with a simple, commercially available molecule of 3-furaldehyde and added other molecules until it matched natural ginkgolide B exactly. Spectroscopic analyses showed the UNC-CH and natural products to be identical.
"The advantage of making the molecule synthetically is that now we can make similar molecules with slightly different structures," Crimmins said. "Some of those could be more active or absorbed better or better tolerated in the body."
He and his students are excited about their success since other chemists will view it as a substantial accomplishment, he said. Using sophisticated and novel techniques, they have re-created a complicated molecule through a relatively short sequence of chemical reactions.
Others involved in the synthesis, all now or formerly at UNC-CH, include postdoctoral fellows Drs. Jennifer Pace, Allan Wagman, Agnes Kim-Meade and Scott Watterson. Former graduate students James Thomas and Philippe Nantermet, who have since earned their Ph.D.s also contributed.
"Our next steps will be to improve the synthesis by making it shorter and more efficient if possible," Crimmins said. "We also probably will look at analogs, or other forms, of the molecule to test their activity in cell culture."
Three years ago, Crimmins and graduate student Bryan W. King reported developing an improved method of synthesizing the desired form of various compounds - including those used to treat AIDS - that occurred in two mirror-image forms. Being able to choose and produce a molecule of a particular structure is important, he said, because sometimes the mirror image is not effective as a drug, and sometimes it is toxic.
The National Institutes of Health and the National Science Foundation supported the research. Crimmins serves as vice chair for graduate studies in UNC-CH's chemistry department.
Note: Crimmins can be reached at 919-962-5177 or via e-mail at: crimmins@email.unc.edu
Contact: David Williamson, 919-962-8596.