SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

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The principal objectives of this program are the synthesis of analogs of disaccharides in which the interglycosidic oxygen atom is replaced by a methylene group, and the evaluation of their activity as glycosidase inhibitors. The scope of the program will be extended, during the next budget period, to a new class of pseudodisaccharides, namely aza-C- disaccharides, in which the ring oxygen atom of the "non-reducing" unit is replaced by an imino (-NH-) group (equivalent to elusive nojirimycin- disaccharides). The specific aims for the next budget period are (1) the preparation of specific branched C-disaccharides (e.g., C-lactosamine), (2) the development of efficient synthetic approaches to aza-C-disaccharides (e.g., aza-C-maltose), and (3) the preparation first examples of pseudotrisaccharides (C,O and O,C-trisaccharides). As chemically inert and structurally extremely similar analogs of the natural substrates of several types of glycosidase, the proposed pseudeooligosaccharides are likely to behave as potent, strictly competitive inhibitors of the hydrolytic process catalyzed by these enzymes. Maltose analogs, in particular, are especially significant targets as potential modulators of carbohydrate metabolism: as highly selective inhibitors of the alpha-glucosidases of the digestive tract, these compounds might provide a means of controlling the intestinal glucose uptake and thus prove useful in the treatment of metabolic diseases such as diabetes mellitus. Furthermore, as potential inhibitors of the "trimming" glycosidase involved in the processing of the oligosaccharide chains of glycoproteins (such as for example of the envelope glycoprotein of the human HIV virus), the proposed pseudodisaccharides (e.g., aza-C- kojibiose) might also posses significant antiviral activities. A major challenge in synthetic carbohydrate chemistry, the synthesis of C-disaccharides require the coupling of two sugar units by a C-C bond forming reaction. Efficient methodologies based on polar (mitroaldol) and radical (SRN1) processes have been developed and have provided expeditious syntheses of linear" C-disaccharides. "Branched" C- disaccharides will be prepared by way of SRN1-coupling processes and aza- C-disaccharides by way of radical or polar coupling processes. The biological activity of the pseudooligosaccharides will be determined in our laboratory using simple glycosidase, and in specialized laboratories using alpha and Beta-glucanases (in collaboration with Dr. H. Driguez, CNRS-Grenoble, and Dr. M. Claeyssens, University of Gent, respectively).