508-93-0Relevant articles and documents
Pregnanes That Bind to the Digitalis Receptor: Synthesis of 14-Hydroxy-5β,14β-pregnane Glycosides from Digitoxin and Digitoxigenin
Templeton, John F.,Setiloane, Peter,Kumar, V. P. Sashi,Yan, Yulin,Zeglam, Talal H.,LaBella, Frank S.
, p. 2778 - 2782 (1991)
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 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.
Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation
Khatri, Hem Raj,Bhattarai, Bijay,Kaplan, Will,Li, Zhongzheng,Curtis Long, Marcus John,Aye, Yimon,Nagorny, Pavel
, p. 4849 - 4860 (2019/03/26)
A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5-epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 μM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.
Stereochemical survey of digitoxin monosaccharides
Wang, Hua-Yu Leo,Xin, Wenjun,Zhou, Maoquan,Stueckle, Todd A.,Rojanasakul, Yon,O'Doherty, George A.
, p. 73 - 78 (2011/04/17)
A stereochemically diverse array of monosaccharide analogues of the trisaccharide-based cardiac glycoside natural product digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against nonsmall cell human lung cancer cells (NCI-H460). The results were compared with digitoxin and its aglycone digitoxigenin. Three novel digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar antiproliferation effects but with at least 5-fold greater potency in apoptosis induction than digitoxin against NCI-H460. This study demonstrates the ability to improve the digitoxin anticancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.
Synthesis and evaluation of the α- D -/α-l-rhamnosyl and amicetosyl digitoxigenin oligomers as antitumor agents
Wang, Hua-Yu Leo,Rojanasakul, Yon,O'Doherty, George A.
scheme or table, p. 264 - 269 (2011/06/17)
A highly regio- and stereoselective asymmetric synthesis of rhamnosyl- and amicetosyl-digitoxigenin analogues has been established via palladium-catalyzed glycosylation followed by bis-/tris-dihydroxylation or bis-/tris-diimide reduction. The α-l-rhamnose and α-l-amicetose digitoxin monosaccharide analogues displayed stronger apoptosis inducing activity and cytotoxicity against nonsmall cell human lung cancer cells (NCI-H460) than its d-diastereomeric isomers in a sugar-chain length dependent manner.
