BIOLOGICAL ACTIVITIES OF CYCLOPHELLITOL

Abstract

Cyclophellitol ((1S, 2R, 3S, 4R, 5R, 6R)-5-hydroxymethyl-7-oxabicyclo[4, l, 0]heptane-2, 3, 4-triol) was tested against 9 glycosidases and found to be a specific inhibitor of almond β-glucosidase. Cyclophellitol inhibited almond β-glucosidase activity by 50% at 0.8 μg/ml and was a competitive inhibitor of almond β-glucosidase as revealed by Lineweaver-Burk plot. Cyclophellitol was inactive against yeast α-glucosidase, β-galactosidase, β-glucuronidase, α-L-fucosidase, end-β-N-acetyl glucosaminidase, α-mannosidase, and cellulase. It was weakly active toward fungal β-xylosidase. Cyclophellitol-treated almond β-glucosidase was equally suppressed after dialysis; thus cyclophellitol is likely to bind to almond β-glucosidase irreversibly. The inhibitor was found by fluorimetric assay to be active against β-glucosidase but inactive toward α-glucosidase in Molt-4 microsomal fraction. It also inhibited Molt-4 β-glucocerebrosidase completely at 2 μg/ml when the enzyme was assayed with a synthetic labeled substrate, and the inhibitory activity was more than one hundred times higher than that of nojirimycin, castanospermine, or of deoxynojirimycin. Mice administered 1 mg of cyclophellitol daily for 5 days began to exhibit severe abnormalities of nervous system similar to those found in GAUCHER'S mouse.