Calystegins, a Novel Class of Alkaloid Glycosidase Inhibitors

Abstract

The alkaloid extract from roots of naturally growing Convolvulus arvensis, purified by ion-exchange chromatography, showed significant inhibitory activity toward β-glucosidase and α-galactosidase. The demonstrated occurrence of polyhydroxy-nortropane alkaloids, the calystegins, in C. arvensis and their structural similarity to known polyhydroxy alkaloid glycosidase inhibitors, suggested that these might be responsible for the observed activity. Pure calystegins, isolated from transformed root cultures of the related plant species Calystegia sepium, were tested for glycosidase inhibitory activity. The purity of the alkaloids was established by gas chromatography and their identity confirmed by their mass spectrometric fragmentation patterns. The trihydroxy alkaloid, calystegin A3, was a moderately good inhibitor of β-glucosidase (Ki = 4.3 × 10−5 M) and a weak inhibitor of α-galactosidase (Ki = 1.9 × 10−4 M). An increased level of hydroxylation, as in the tetrahydroxy calystegins B, consisting of 27% calystegin B1 and 73% calystegin B2, resulted in greatly enhanced inhibitory activity. The calystegins B were potent inhibitors of β-glucosidase (Ki = 3 × 10−6 M) and α-galactosidase (Ki = 7 × 10−6 M). These levels of activity are comparable with those of the polyhydroxy indolizidine alkaloids castanospermine and swainsonine toward α-glucosidase and amannosidase, respectively, and of the polyhydroxy pyrrolizidine alkaloid australine toward α-glucosidase. The calystegins therefore compose a new structural class of polyhydroxy alkaloids, the nortropanes, possessing potent glycosidase inhibitory properties.