1672-46-4Relevant academic research and scientific papers
Metabolism of digoxin and digoxigenin digitoxosides in rat liver microsomes: Involvement of cytochrome P4503A
Salphati, Laurent,Benet, Leslie Z.
, p. 171 - 185 (1999)
1. The sequential metabolism of digoxin (Dg3) to digoxigenin bis-digitoxoside (Dg2), digoxigenin mono-digitoxoside (Dg1) and digoxigenin (Dg0) was investigated in rat liver microsomes. 2. Kinetic studies produced results consistent with a single enzyme mechanism describing the successive oxidative cleavages. Formation of Dg2 was catalysed with mean (± SD) K(m) and V(max) of 125 ± 22 μM and 362 ± 37 pmol/min/mg protein, respectively. The corresponding values for the formation of Dg1 were 61 ± 5 μM and 7 ± 1 pmol/min/mg protein. Dg0 formation was catalysed with the apparent values of 30 ± 9 μM and 310 ± 30 pmol/min/mg protein. 3. Chemical inhibition of cytochrome P450 (CYP) 3A subfamily with ketoconazole and triacetyoleandomycin decreased the formation of Dg2 and Dg1 by up to 90%. Antibodies specific to rat CYP3A2 lowered the rate of oxidative cleavage of Dg3 and Dg2 by up to 85%. Inhibition of CYP2E1, CYP2C subfamily and CYP1A2 by chemical and immunoinhibition did not affect initial rates of metabolism of Dg3 and Dg2. In contrast, Dg1 metabolism was not affected by triacetyloleandomycin as well as by antibodies to CYP3A2, CYP2C11, CYP2E1, CYP2B1/2B2 and CYP1A2. It was however inhibited by > 80% by gestodene and 17α-ethynylestradiol (selective inhibitors of human CYP3A). 4. Collectively, these data support the involvement of CYP3A in the cleavage of Dg3 and Dg2 in rat liver microsomes. The enzyme-metabolizing Dg1 remains to be identified.
Biotransformation of extracted digitoxin from Digitalis lanata by Streptomyces
Keshk, Sherif,Mostafa,Tawfik,Elshemy
, p. 458 - 462 (2011)
The biotransformation of digitoxin and some of its derivatives extracted from Digitalis lanata by Streptomyces isolated species was investigated. Cultures of a Streptomyces strain designated EUSA-2003B, isolated from an Egyptian soil sample, efficiently induced selective 12β-hydroxylation of the steroid aglycone of digitoxin (DT) and its α-acetyl and β-methyl derivatives. The transformation reaction was performed within a 5-day fermentation process, products were isolated and their aglycone moiety was obtained by acid hydrolysis and their structures were elucidated by 13C and 1H NMR. The biotransformation resulted mainly digoxin (DG,～87%), meanwhile, digoxigenone (DGON,～7.0%)was also afforded as a side product. The present study revealed that: 1-Streptomyces isolate EUSA2003B harbors its specific 12β-hydroxlase and has the capability to transform DT and it's α-acetyl and α-methyl derivatives into their corresponding digoxins at reasonable yields. 2-The minor structural differences in the trisaccharide side chain seemed ineffective on the transformational capability of this organism. 3-The Streptomyces might also possess a specific glycosidase that splits the saccharidic side chain beside another dehydrogenase that oxidizes C3 at the steroid nucleus into its ketone form (DGON).
Na+/K+-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives
Burdette, Joanna E.,Chen, Xiaozhuo,Cheng, Xiaolin,Heath, Kimberly,Johnson, Michael E.,Kinghorn, A. Douglas,Ren, Jinhong,Ren, Yulin,Ribas, Hennrique T.,Shriwas, Pratik,Wu, Sijin
, (2020/03/05)
(+)-Digoxin (1) is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (2-5) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin (6) and (+)-17-epi-20,22-dihydro-21α-hydroxydigoxin (7), were synthesized from 1 and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for 1 to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic 1 and the noncytotoxic derivative 7 bind differentially to Na+/K+-ATPase. The HO-12β, HO-14β, and HO-3′aα hydroxy groups of (+)-digoxin (1) may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na+/K+-ATPase, respectively, but the altered lactone unit of 7 results in a rotation of its steroid core, which depotentiates the binding between this compound and Na+/K+-ATPase. Thus, 1 was found to inhibit Na+/K+-ATPase, but 7 did not. In addition, the cytotoxic 1 did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.
17BETA-HETEROCYCLYL-DIGITALIS LIKE COMPOUNDS FOR THE TREATMENT OF HEART FAILURE
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Page/Page column 0149; 0150; 0151, (2020/02/13)
Disclosed are compounds of formula (I) wherein X, Y, Z are annular atoms comprised in a five-membered carbocyclic or heterocyclic ring, selected from the group consisting of CH, NH, N, O, S; said carbocyclic or heterocyclic ring being optionally substituted with amino (C1-C4) linear or branched alkyl or guanidine or guanidino (C1-C4) linear or branched alkyl; with the proviso that the heterocycle ring is not furyl; n is 0 or 1; R is H or OH; the dotted line represents an optional double bond C=C; the thick line represents a bond in the β configuration; the wavy line represents a bond both in the α and β configuration; their enantiomeric and/or diastereomeric mixtures, their pharmaceutically acceptable salts, their solvates, hydrates; their metabolite and metabolic precursors. The compounds of formula (I) are for use as medicaments, in particular for the treatment of acute or chronic heart failure. Oral administration is also possible.
Effect of cyclodextrins on the acid hydrolysis of digoxin.
Uekama,Fujinaga,Hirayama,Otagiri,Kurono,Ikeda
, p. 627 - 630 (2007/10/02)
The effects of three cyclodextrins (alpha-, beta-, gamma-CyD) on the acid hydrolysis of digoxin were examined. From the high performance liquid chromatographic tracing of each of the four components (digoxin, bisdigitoxoside, monodigitoxoside, digoxigenin) in reaction mixtures, the individual rate constants (K1-K6) were determined by analogue computer simulation. The hydrolysis was suppressed by CyDs in the order of beta-great than gamma-greater than alpha-greater than-CyD, where beta-CyD inhibited the appearance rates of digoxigenin (k3, K5, and K6) significantly. In the dissolution study of digoxin tablets, the increase in dissolution rate and decrease in acid hydrolysis were attained by inclusion complexation. The data are presented suggesting that CyDs are useful for improving the oral bioavailability of digoxin.
14β-HYDROXY STEROIDS-III. SYNTHESIS OF DIGOXIGENIN FROM DEOXYCHOLIC ACID
Welzel, Peter,Stein, Hermann
, p. 3385 - 3388 (2007/10/02)
A new synthetic approach to cardenolides is discussed which employs singlet oxygen addition to dienol ethers and an intramolecular Prins reaction.
14 β-Hydroxy 3-deoxycardenolides
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, (2008/06/13)
Novel compounds of the formula STR1 useful as pharmaceutical compounds are disclosed. Processes are also disclosed for their preparation.
