Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs

Article abstract of DOI:10.1016/j.bmc.2011.02.016

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 (IC₅₀ 0.24 μM), which was slightly better than digitoxigenin (IC₅₀ 0.64 μM), while none of the novel cardiac glycoside mimics display an in vitro effect as high as digitoxin (IC₅₀ 0.02 μM).