Synthesis of glycosaminoglycan mimetics through sulfation of polyphenols.

In nearly all cases of biological activity of sulfated GAGs, the sulfate group(s) are critical for interacting with target proteins. A growing paradigm is that appropriate small, sulfated, nonsaccharide GAG mimetics can be designed to either mimic or interfere with the biological functions of natural GAG sequences resulting in the discovery of either antagonist or agonist agents. A number of times these sulfated NSGMs can be computationally designed based on the parent GAG-protein interaction. The small sulfated NSGMs may possess considerable aromatic character so as to engineer hydrophobic, hydrogen-bonding, Coulombic or cation-pi forces in their interactions with target protein(s) resulting in higher specificity of action relative to parent GAGs. The sulfated NSGMs can be easily synthesized in one step from appropriate natural polyphenols through chemical sulfation under microwave-based conditions. We describe step-by-step procedures to perform microwave-based sulfation of several small polyphenol scaffolds so as to prepare homogenous NSGMs containing one to more than 10 sulfate groups per molecule in high yields.