Mini-Reviews in Medicinal Chemistry, 2009, 9, 169-185 169 1389-5575/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Solid-Phase Synthesis of Oligosaccharide Drugs: A Review Meenakshi Dhanawat * and Sushant Kumar Shrivastava Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, -221005, India Abstract: Solid- phase synthesis is an approach, where synthetic transformation in carbohydrates are carried out with one of the reactant molecule attached to an insoluble material referred as polymeric support via linker. In recent years, it has been extensively accepted as fast and accurate method for the synthesis of biologically active oligosaccharides. This re- view attempts to focus on various methods of oligosaccharide synthesis by solid- phase including their applications. Key Words: Carbohydrate, oligosaccharide, biologically active, solid- phase synthesis, linkers, protecting groups, glycosylat- ing agents. 1. INTRODUCTION Oligosaccharides play an important role in many bio- chemical recognition processes and synthetic analogs to these natural biopolymers could be used to study the influ- ence or even control to these biochemical processes. Hence, they hold great potential as therapeutic agents. The limited availability of complex oligosaccharides is a reason for the major impediment in the study of carbohydrates. In the recent years, development of efficient and yet sim- ple procedures for the synthesis of oligosaccharides has been a major goal of carbohydrate chemistry. It is highly desirable to establish methodology for rapid oligosaccharide assembly. Several methods and strategies have been developed so far, which include synthesis in the solution phase leading to ste- reo controlled and high yield reactions. Chemical and enzy- matic synthesis of oligosaccharides on soluble or insoluble polymeric support has also been reported. The advantages associated with the use of an insoluble polymeric support justify further efforts to improve the solid phase strategy. The solid- phase synthesis has been demonstrated to be extremely valuable for routine preparation of oligopeptides and oligonucleotides. The potential usefulness of this proce- dure for the synthesis of other biomolecules is obvious. In past few years, the interest in solid-phase synthesis has in- creased dramatically due to the excitement engendered by the concept of combinatorial chemistry. The Solid-phase synthesis of oligosaccharides, when carried out combinatori- aly, offers the possibility of easy access to a very large num- ber of well-defined oligosaccharides. This can be used as potential tools in glycobiology [1-5]. 2. PRINCIPLES OF OLIGOSACCHARIDE SYNTHE- SIS A number of methods for the synthesis of oligosaccha- rides have been developed in the recent years which involve stereo controlled and high yield reactions [6]. One of the key difficulty in synthesizing oligosaccharides is ensuring the *Address correspondence to this author at the Department of Pharmaceutics, Institute of Technology, Banaras Hindu University Varanasi, -22100, India; Tel: 09794343787; E-mail: meenakshi.itbhu@gmail.com stereochemistry of the glycosidic linkages (anomeric centre) – the carbon-oxygen-carbon bridges between the sugar units and presence of multiple reactive sites Fig. (1) [7]. A glyco- syl donor couples with acceptor at the anomeric centre re- sulting in either or stereochemistry [5]. Oligosaccharides can be synthesized chemically or enzymatically depending upon the reagent used. Fig. (1). Monosaccharide contains multiple reactive sites and an anomeric carbon. 2.1. Chemical Synthesis Chemical synthesis, also called classical multi-step ap- proach is advantageous as it provides homogeneous com- pounds in substantial quantity. Though the method provides almost unlimited flexibility to synthesize various structures including non-natural ones, it requires multi-step transforma- tions, complicated protecting group pattern and tedious chromatographic purification after each step, hence making it time consuming and technically not demanding for large scale production [8]. 2.2. Enzymatic Synthesis This method is an alternative to chemical oligosaccharide synthesis and includes both glycosyltransferases (catalyst) and glycosidase where nucleotide sugars are the donors [9]. Glycosyltransferases show high regio- and stereo- selectivity along with elimination of protection and deprotection steps [10].On combination with solid-phase techniques, the method offers particularly a simple way to synthesize oligosaccha- rides on a laboratory scale [8]. Availability of the glycosyl donor, substrate tolerance and cost factor are the limitations which hampers its use on large scale [10]. The substrate specificity of the glycosyltransferases can be modified, improved or changed in order to create new O HO HO OR HO OH 1 2 3 4 5 6 Seconary hydroxyl with differing reactivity Anomeric carbon (axia)l or (equitorial) stereochemistry