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UW-Madison scientists zero in on drugs' sweet spots

Employing a simple new technique to manipulate the sugars that power many front-line drugs, a team of Wisconsin scientists has enhanced the antic-cancer properties of a digitalis, a drug commonly used to treat heart disease.

Reporting the work in the Aug. 8 edition of the Proceedings of the National Academy of Sciences, a team led by University of Wisconsin-Madison professor of pharmaceutical sciences Jon S. Thorson, describes a series of experiments that boosted the cell-killing potency and tumor specificity of the drug, derived from the foxglove plant and used to stimulate the heart. The drug is suspected to have anti-cancer properties, but its use to treat cancer has been little explored.

The new work is important because it provides scientists and drug companies with a quick and easy way to manipulate the sugars found in chemicals produced in nature. Such chemicals -- often found in microbes, plants and marine organisms -- are the bedrock agents upon which many leading drugs are built. The ways sugar groups are organized on a molecule often dictate the agent's biological effects.

"In the past, to alter the sugars attached to these drugs was very difficult," explains Thorson, of the UW-Madison Pharmacy School's Laboratory for Biosynthetic Chemistry. "These are very complex molecules."

The new technique replaces enzymes, biological catalysts, with a robust chemical method, allowing researchers to easily manipulate and exchange the sugars found in natural agents.

Critically, the method allows medicinal chemists to investigate the biological effects of the many forms of sugars or carbohydrates found in nature. "There are many different variations of sugars -- they're all over the place in nature -- and they are very important. This method allows us to rapidly scan the roles of these sugars in complex natural products."

The simplification of the process to manipulate natural sugars could help make natural products more a ppealing to the pharmaceutical industry. Despite the fact that 60-75 percent of drugs approved to treat infectious disease and cancer over the past 25 years are of natural origin, many companies have lost interest in developing natural products because of the complex chemistry that underpins them.

The ability to zero in on the sweet spot of drugs derived from natural products promises to help scientists specify the role of the sugar and make new drugs or enhance old ones to greater precision and effect. The series of experiments performed by Thorson's team, for example, may help researchers enhance the anti-cancer effects of digitalis and downshift its influence on the heart, thus avoiding potential detrimental effects in cancer patients.

"I think this (technique) is going to send us down some interesting mechanistic roads," Thorson notes. "Digitalis hasn't been aggressively pursued as an anti-cancer agent."

According to Thorson, the technology can be widely applied: "We've already taken this chemistry and applied it to many different drug classes. It's possible to extend it to antibiotics and antivirals. If you want to plug in a sugar and see what it does for you, this is the best way to do it."

The new technique, according to Thorson, will play a prominent role in the new UW-Madison National Cooperative Drug Discovery Group, a consortium of UW-Madison scientists seeking to develop new anti-cancer drugs from natural products. The group was recently formed with the help of a $5.6 million grant from the National Cancer Institute (NCI).

The new work by Thorson was supported by the National Institutes of Health and the NCI. Thorson's collaborators include Joseph Langenhan, a former UW-Madison graduate student and post-doctoral fellow and now a chemistry professor at Seattle University; Noel R. Peters, and Professor F. Michael Hoffmann of the UW-Madison Comprehensive Cancer Center's Small Molecule Screening Facility; and Ilia A. G uzei, director of crystallography in the UW-Madison department of chemistry.


Source:University of Wisconsin-Madison

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