Inhibitors of glycosidase activity

Claeyssens, M, De Bmyne, C K, D-Xylose-derivatives with sulfur or nitrogen in the ring powerful inhibitors of glycosidase-activities, Naturwissenschaften, 52, 515, 1965. 

Polyhydroxyalkaloids which structurally resemble monosaccharides have been found in a variety of organisms, including higher plants. Many are potent inhibitors of glycosidase activity in insects, mammals and microorganisms and it is suggested that these properties contribute to the natural chemical defences of those plants in which they accumulate. 

Aspidiaceae (Fellows et al., 1986 Janzen et al., 1990). These compounds are similar in some regards to coniine (48), a nonhydroxylated piperidine alkaloid. In some legumes, polyhydroxy piperidine alkaloids make up as much as 2% of the dry weight of the plant. These compounds are similar structurally to sugars and are potent inhibitors of glycosidase activity. Specificity varies and some compounds of this series inhibit mannosidases, others fucosidases, and so forth. No glucosidase inhibitor has been reported to present (Fellows et al., 1986) (also see Chapter 15). 

Castanospermine and several other polyhydroxyalkaloids known to act as glycosidase inhibitors have been used for the characterisation and differentiation of glycosidase activity in insects [172,173] and degradation of residual oligomannosides resulting from the cytosolic deglycosylation of newly synthesised glycoproteins [174-176]. 

Glycosyl methyl-/ nitrophenyl triazenes have been shown to be very effective and specific irreversible inhibitors of glycosidases, which remove the appropriate sugar to expose the highly reactive triazene, that is, they cause a form of lethal metabolism (Sinnott and Smith, 1976, 1978 van Diggelen et al, 1980). These substrates are useful in vitro and should prove of great value in the analysis of the mechanisms of glycosidase activity. They are not toxic to whole cells and so are presumably not taken up. 

Trihydroxyazepanes (trideoxy-l,6-iminohexitols) have also been prepared from carbohydrate precursors and activities as inhibitors of selected glycosidase enzymes assessed... 

Cycloaddition reaction of nitrone (—)-(394) with dimethyl maleate D14 has been used for the synthesis of two new polyhydroxyl pyrrolizidines (687) and (688) (Schemes 2.293, 2.294). These compounds are analogs of alkaloids ros-marinecine and crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)- a-epi-crotanecine) (—)-(688) is a potent and selective inhibitor of a-mannosidases (310). The reaction of (—)-(394) with dimethyl maleate gave a 9.6 6 1 mixture of cycloadducts (—)-(680), (+ )-(680), and (—)-(681), which arise from anti-exo,... 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

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