Glycosamino Acids: Building Blocks for Combinatorial Synthesis-Implications for Drug Discovery

The unique functions of carbohydrates, including energy storage, transport, modulation of protein function, intercellular adhesion, signal transduction, malignant transformation, and viral and bacterial cell–surface recognition, underlie a significant pharmaceutical potential. The development of combinatorial carbohydrate libraries in this important arena has been slow, in contrast to the rapid development of combinatorial synthesis in the area of small‐molecule libraries and biopolymers. This is largely as a result of the inherent difficulties presented by this class of polyfunctional compounds. Nevertheless, strategies to cope with these problems have been devised over the past seven years, and combinatorial carbohydrate libraries have appeared. The incorporation of an amino acid moiety into the carbohydrate scaffold generates glycosamino acids, which are attractive building blocks for the preparation of carbohydrate‐based libraries because of the well‐established automated peptide synthesis. Derivatization as well as homo‐ and heterooligomerization of glycosamino acids can be used to create novel structures with unique properties. Glycosamino acids are hybrid structures of carbohydrates and amino acids which can be utilized to generate potential glycomimetics and peptidomimetics. The incorporation of glycosamino acids into peptides allows the engineering of carbohydrate‐binding sites into synthetic polypeptides, which may also influence the pharmacokinetic and dynamic properties of the peptides. Furthermore, sugar–amino acid hybrids offer a tremendous structural and functional diversity, which is largely unexplored and requires combinatorial strategies for efficient exploitation. This article provides an overview of previous work on glycosamino acids and discusses their use in combinatorial synthesis and drug discovery. Sugar–amino acid hybrids combine the molecular features of amino acids and carbohydrates. These hybrids (see picture) are attractive building blocks and scaffolds for combinatorial synthesis because of their polyfunctional nature. Oligomerization and derivatization of these hybrids have resulted in novel glycomimetics, peptidomimetics, and biopolymers, many of which are biologically active.