Recent work has shown that glycosaminoglycans (GAGs) are involved in the regulation of manyphysiological processes, including human development, viral invasion, neuronal growth, and cancermetastasis. Initial evidence also suggests that the physiological message sent by cells is largely determinedby the sulfation pattern of these polysaccharides. Attempts to study this 'sulfation code' have been hinderedby the difficulty in obtaining homogenously sulfated GAGs. Genetic and biochemical methods producemixtures of products. Furthermore, no general or selective synthetic methods are available for the selectivesulfation of polyol compounds. In this proposal, a plan to eliminate this obstacle is outlined. The majorobjectives of the following proposal are threefold: (1) To develop regioselective methods for the sulfation orsulfonylation of one alcohol in a polyol using oligopeptide-based catalysts with modified histidine residues;(2) to apply this sulfonyl transfer catalyst to the functionalization of sugars and the synthesis of sulfatedsugars, aminoglycans, and deoxysaccharides; (3) to probe the biological significance of specific sulfationpatterns of GAGs using a library of oligosaccharides derived from these sugar derivatives. The first step inthis plan is to expand a technique to selectively acylate carbohydrates that the Miller group has recentlydeveloped to allow for the sulfation and sulfonylation of alcohols. Using rational design of (5-turn peptideswith modified histidine residues, hydrogen-bonding interactions will be engineered between the peptidecatalyst and the carbohydrate substrate to achieve the desired selectivity. Once a moderately selectivecatalyst has been identified, kinetics and NMR conformational analysis will be used to elucidate the origin ofthe selectivity and design improved catalysts. In this manner, a series of catalysts will be developed toselectively sulfate or sulfonylate each position of relevant monosaccharides. The sulfonylated products willbe further transformed into amino- or deoxysugars, as well as other sugar derivatives. Using thesetechniques, a library of sugars will be synthesized and used to construct novel GAG analogs.Complex sugars containing negatively-charged sulfate groups, known as sulfated polysaccharides, havebeen implicated in the control of many physiological processes, including human development, viralinvasion, neuronal growth, and the growth and spread of cancer. The pattern of negative charges in thesecomplex sugars is thought to act as a regulatory code in the body. By developing a method to provide moreefficient access to sulfated polysaccharides, this work will facilitate the understanding of this sulfation code.
