|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Inhibitors against glycosyltransferases and glycosidases, which build up oligosaccharide moieties of biologically active glycoconjugates, are essential tools for the development of glycobiology and promising candidates of novel agents for the treatments of tumors, inflammatory, autoimmune diseases, and bacterial and virus infections. Many excellent inhibitors against glycosidases, such as deoxynojirimycin and oseltamivir, were found from nature and developed by good combination of structural biology and synthetic chemistry. However, excellent inhibitors of glycosyltransferases have not been developed until recently, because of little information on the structures of active sites of the enzymes, involvement of several components in the transition state of the enzyme catalyzed reaction, low affinities between the enzymes and substrates, and no facile assay systems for the inhibitory activities. Therefore, we embarked on design and synthesis of sugar nucleotide analogues as the inhibitors against glycosyltransferases since the sugar nulcleotides are donor substrates of the enzymes. Fortunately, nikkomycin and polyoxins, peptidic analogues of sugar nucleotide are already used practically for the treatment of some skin diseases caused by Candida sp. and as agrochemicals. Thus, we started these compounds by using L-threonine aldolase-catalyzed enzymatic aldol reaction, which afford fl-hydroxy-cc-L-amino acids under completely physiological conditions. Finally, we succeeded in the formal total synthesis of polyoxin C in good overall yield in the shortest step within those reported so far. In addition, a trisaccharide which could be an acceptor substrate of N-acetylglucosaminyltransferase V was faciley synthesized by using thioglycosyl donor, which was prepared by using novel odorless benzenethiols.