The
cardiac glycoside digitoxin, consisting of a
steroid core linked to a labile
trisaccharide, has been used for centuries for the treatment of
congestive heart failure. The well known pharmacological effect is a result of the ability of
cardiac glycosides to inhibit the Na(+), K(+)-
ATPase. Within recent years
cardiac glycosides have furthermore been suggested to possess valuable anticancer activity. To mimic the labile
trisaccharide of
digitoxin with a stabile
carbohydrate surrogate, we have used
sulfur linked
ethylene glycol moieties of varying length (mono-, di-, tri- or tetra-
ethylene glycol), and furthermore used these linkers as handles for the synthesis of bivalent
steroids. The prepared compounds were evaluated for their potencies to inhibit the Na(+), K(+)-
ATPase and for their cytotoxic effect on cancerous MCF-7 cells. A clear trend is observed in both inhibition and cytotoxic effect, where the bioactivity decreases as the size increases. The most potent Na(+), K(+)-
ATPase inhibitors are the compounds with the shortest
ethylene glycol chain (K(app) 0.48 μM) and thiodigitoxigenin (K(app) 0.42 μM), which both are comparable with
digitoxigenin (K(app) 0.52 μM). For the
cancer cell viability assay the shortest mimics were found to have highest efficacy, with the best
ligand having a
monoethylene glycol unit (IC(50) 0.24 μM), which was slightly better than
digitoxigenin (IC(50) 0.64 μM), while none of the novel
cardiac glycoside mimics display an in vitro effect as high as
digitoxin (IC(50) 0.02 μM).