Decorating with Sugars Made Easy

CARBOHYDRATE CHEMISTRY

A new chemical approach speeds up the process of creating natural-product-like compounds decorated with various sugars. The technique creates glycorandomized libraries--diverse carbohydrate-containing compounds that can be screened for interesting biological properties, including possible use as drugs.

"Neoglycorandomization" was developed by pharmaceutical sciences professor Jon S. Thorson of the University of Wisconsin, Madison, and coworkers, including postdoc Joseph M. Langenhan, now assistant professor of chemistry at Seattle University, in Washington (Proc. Natl. Acad. Sci. USA, published online, www.pnas.org/cgi/doi/10.1073/pnas.0503270102). They used the method to convert the heart drug digitoxin into an analog that has anticancer activity instead.

Neoglycorandomization is a simpler chemical version of glycorandomization, a chemoenzymatic approach that Thorson and coworkers developed in 2001. In glycorandomization, sugar phosphates are made from sugars by chemical or chemoenzymatic processes and then treated with sugar activation enzymes to create activated products. Glycosyltransferases are then used to attach the activated sugars to noncarbohydrates (aglycons). The whole process requires multiple steps and is limited to cases in which the enzymes recognize the sugars and aglycons as substrates.

Neoglycorandomization accomplishes sugar ligation chemically without enzymes or sugar activation. In the technique, N-glycosidic bonds are formed between sugars and alkoxyamine groups added to aglycons, a reaction reported earlier by chemistry professor Pascal Dumy of Joseph Fourier University, Grenoble, France, and coworkers.

Thorson and coworkers synthesized 78 digitoxin derivatives by neoglycorandomization and screened them for activity. One analog of the heart drug was a potent cytotoxin against six cell lines, and another was less potent but more highly selective for a multi-drug-resistant cancer cell line.

The researchers show the technique "can be a powerful method to attach things and actually get pharmaceutically relevant and interesting results," says associate professor Michael R. Carrasco of Santa Clara University.

Assistant professor of chemistry David L. Van Vranken of the University of California, Irvine, says, "The work is likely to accelerate studies of small-molecule glycoconjugates."

Glycosylated compounds can also be made by chemical synthesis, which is difficult and time-consuming, and by microbial pathway engineering and bioconversion (genetic modification of natural product biosynthetic pathways to produce nonnatural analogs). Thorson believes neoglycorandomization is much more practical than carbohydrate synthesis and will complement engineering and bioconversion for synthesizing natural-sugar-containing compounds but is "the only effective method" for making nonnatural-sugar-based libraries.

"We have collaborations with other academic groups to explore this technology in the context of other types of glycomolecules, such as oligosaccharides and glycoproteins," Thorson says. The technique has been patented by the Wisconsin Alumni Research Foundation and has been licensed for drug discovery to zuChem, Chicago.