Synthesis of novel glycosidase inhibitors for prevention of angiogenesis and tumor growth

Abstract

Hydroxylated chiral pyrrolidines and piperidines, commonly known as imino- or azasugars, are of significant interest because of their known resistance to enzymatic hydrolysis and their frequent occurrence in biologically active natural products. Glycosidases, enzymes responsible for the cleavage of glycosidic bonds, are involved in the catabolism of glycoconjugates; conversely, glycosyltransferases are involved in the formation of glycosidic bonds. Glycomimetics that inhibit glycosidases and glycosyltransferases therefore display diverse therapeutic applications to carbohydrate-mediated diseases because of their structural resemblance to the sugar moiety of natural substrates of these enzymes, thus altering the catabolism or glycosylation of glycoproteins, or masking the recognition of specific carbohydrates. Glycosidase inhibitors show promise as antiangiogenic and antitumorogenic compounds. We have developed new synthetic routes for preparing glycosidase inhibitors from relatively inexpensive, natural products which affords novel compounds in overall high yield. Compounds will be evaluated for specific glycosidase inhibitory activity. Further, we will use pulmonary microvascular endothelial cells to determine the efficacy of these compounds in prevention of capillary tube formation.