Pregnanes That Bind to the Digitalis Receptor: Synthesis of 14-Hydroxy-5β,14β-pregnane Glycosides from Digitoxin and Digitoxigenin

Article abstract of DOI:10.1021/jm00113a015

The preparation of the mono-, bis-, and trisdigitoxosides of 14-hydroxy-5β,14β-pregnan-20-one and 14,20β-dihydroxy-5β,14β-pregnane by two routes, based on the conversion of the α,β-unsaturated γ-lactone in digitoxin to the 20-ketone and 20β-alcohol by ozonolysis and zinc-acetic acid treatment followed by lithium tri-tert-butoxyaluminum hydride reduction, are described.Synthesis of the α-L-rhamnoside derivatives is described also.Structures were confirmed by 1H and 13C NMR spectra.These derivatives show strong interaction with the cardiac glycoside receptor of heart muscle in an <3H>ouabain radioligand binding assay.Structure-activity relationships which are reported for glycosides and genins show that the α-L-rhamnoside derivatives are more potent than the β-D-digitoxoside or the β-D-glucoside and that the β-D-glucosides are more potent than the mono-, bis-, and trisdigitoxosides.Potency is not increased by the addition of the second and third digitoxose units.