title: Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs.
abstract: 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).
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Jensen
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmidt
authors.forename: Natalya U
authors.initials: NU
authors.lastname: Fedosova
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D004074:Digitoxin / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004074:Digitoxin; D000254:Sodium-Potassium-Exchanging ATPase