November 8, 2006

Carbohydrates

Largest Synthetic Hetero-Oligosaccharide

Milestone could lead to better understanding of major bacterial diseases

Stu Borman

Researchers have succeeded in constructing the largest ever synthetic hetero-oligosaccharide, a carbohydrate containing different kinds of sugar units. The 28-unit structure, a lipoarabinomannan (LAM), is part of the cell-surface oligosaccharide of mycobacterial species that cause a range of diseases, including tuberculosis and leprosy.

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Synthetic The newly synthesized LAM contains 28 sugar residues, including four mannose caps (green) like those present in tuberculosis bacteria. The arabinan domain is red, and the mannan core is blue. Bn (benzyl ether) and Bz (benzoyl ester) are protecting groups.

The natural product cannot easily be derived in pure form from bacteria, so a synthetic route is desirable. The synthesized structure lacks sugar residues and linkages and a series of dangling lipids found in the complete natural product.

The synthesis could lead to a deeper understanding of the mechanism of mycobacterial infections and of LAM's biological activities, which include immunomodulatory effects and intracellular signaling. The work also could help lead to the synthesis of the entire lipidated cell-surface oligosaccharide, which contains 60–70 sugar residues.

The research was carried out by carbohydrate chemist Bert Fraser-Reid, postdocs Jun Lu and K. N. Jayaprakash, and visiting professor J. Cristóbal López at the Natural Products & Glycotechnology Research Institute, Pittsboro, N.C. (Tetrahedron: Asymmetry 2006, 17, 2449). The institute is a private, nonprofit research organization with laboratories at the Centennial Campus of North Carolina State University, Raleigh, N.C.

Fraser-Reid and coworkers earlier reported having synthesized the 12-sugar lipomannan segment of the cell-surface oligosaccharide (Angew. Chem. Int. Ed. 2005, 44, 5894; C&EN, Sept. 19, 2005, page 38), but this represented less than half of the new structure.

The rest of the new structure consists of a large arabinan domain, which includes a series of furanose sugars and a set of sugar "caps." The furanoses were the most challenging part of the synthesis. "Furanose sugars have received comparatively little attention," Fraser-Reid says. "Our methodology has revolutionized how these are put together."

The lipidless 28-mer structure the researchers have synthesized varies only a little among different types of mycobacteria, but the caps differ from one species to another and determine the oligosaccharide's biological specificity. In the synthetic LAM, Fraser-Reid and coworkers used mannose caps, the type present in Mycobacterium tuberculosis.

"Apart from this being a world record for hetero-oligosaccharide synthesis, it is also a superb piece of work," comments organic chemistry professor Steven V. Ley of Cambridge University, a specialist in natural product synthesis. "It's beautifully planned, and it really shows the power of modern-day oligosaccharide synthesis."

Synthetic carbohydrate chemist Todd L. Lowary of the University of Alberta says, "This is an impressive synthetic achievement. Access to oligosaccharide fragments of LAM using approaches such as this will be essential in providing a molecular-level understanding of the role of this polysaccharide in mycobacterial pathogenesis."

Professor of microbiology, immunology, and pathology Delphi Chatterjee of Colorado State University, who specializes in mycobacterial carbohydrates, notes that Fraser-Reid and coworkers incorporated α-linked furanoses in their structure instead of much more synthetically challenging β-linked furanoses present in the natural product. "So the synthesized molecule is not the real LAM structure present in the M. tuberculosis cell wall," she says. In the future, the researchers "will need to modify this molecular structure to match the real molecule in mycobacteria."

That said, the new synthesis is still "one of the most difficult and meaningful tasks in the history of carbohydrate chemical synthesis," Chatterjee adds.

Chemical & Engineering News

ISSN 0009-2347

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