title: Pregnanes that bind to the digitalis receptor: synthesis of 14-hydroxy-5 beta,14 beta-pregnane glycosides from digitoxin and digitoxigenin.
abstract: The preparation of the mono-, bis-, and trisdigitoxosides of 14-hydroxy-5 beta,14 beta-pregnan-20-one and 14,20 beta-dihydroxy-5 beta,14 beta-pregnane by two routes, based on the conversion of the alpha,beta-unsaturated gamma-lactone in digitoxin to the 20-ketone and 20 beta-alcohol by ozonolysis and zinc-acetic acid treatment followed by lithium tri-tert-butoxyaluminum hydride reduction, are described. Synthesis of the alpha-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 alpha-L-rhamnoside derivatives are more potent than the beta-D-digitoxoside or the beta-D-glucoside and that the beta-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.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Templeton
authors.forename: P
authors.initials: P
authors.lastname: Setiloane
authors.forename: V P
authors.initials: VP
authors.lastname: Kumar
authors.forename: Y L
authors.initials: YL
authors.lastname: Yan
authors.forename: T H
authors.initials: TH
authors.lastname: Zeglam
authors.forename: F S
authors.initials: FS
authors.lastname: LaBella
mesh_terms: D004070:Digitalis / Q000378:metabolism*; D004073:Digitoxigenin / Q000737:chemistry*; D004074:Digitoxin / Q000737:chemistry*; D006027:Glycosides / Q000138:chemical synthesis / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010946:Plants, Medicinal; D010947:Plants, Toxic; D011278:Pregnanes / Q000138:chemical synthesis* / Q000378:metabolism; D011869:Radioligand Assay; D011955:Receptors, Drug / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase
chemical_list: D006027:Glycosides; D011278:Pregnanes; D011955:Receptors, Drug; C027082:digitalis receptor; D004073:Digitoxigenin; D004074:Digitoxin; D000254:Sodium-Potassium-Exchanging ATPase