Selective Inhibition of Glycosidases by Feedback Prodrugs

摘要

Protein- and lipid-linked oligosaccharides at the surface of eukaryotic cells are responsible for a wide range of biological processes impacting health and disease.[1]-[4] Examples of such processes include fertilization, embryogenesis, neuronal development, hormone activities, and the proliferation of cells and their organization into specific tissues. Remarkable changes in cell-surface carbohydrates occur with tumor progression, which appears to be intimately associated with the dreaded state of metastasis.[5]-[7] Furthermore, carbohydrates of host cells are often employed by pathogens for cell entry. Not surprisingly, compounds that can interfere in the biosynthesis of oligosaccharides are regarded as attractive leads for drug discovery for a wide range of diseases.[8]-[14] For example, inhibitors of pancreatic -amylase, such as arcarbose, voglibose, and miglitol, have been introduced for the treatment of diabetes.[15] Furthermore, compounds such as zamamivir and oseltamivir (tamiflu) have been developed as inhibitors of neuramidase for the treatment of the flu.[16]-[20] Despite these successes, it has been difficult to develop safe and efficacious glycosidase inhibitors for the treatment of many other diseases. A major problem of many natural and synthetic glycosidase inhibitors is that they inhibit other glycosidases, which may lead to serious side effects. More-selective inhibitors may be obtained by carefully designed structure - activity-relationship studies[21]-[29] in combination with a better understanding of the mechanism of action of glycosidases. This approach is, however, complicated by the fact that of the approximate 100 mammalian glycosidases, only a small number have been cloned and overexpressed.