Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na<sup>+</sup>,K<sup>+</sup>-ATPase Receptor

Cerri, Alberto; Serra, F.P.; Ferrari, Paolo; Folpini, Elena; Padoani, Gloria; Melloni, P.

doi:10.1021/jm970312l

Cited by 23 publications

(23 citation statements)

References 15 publications

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“…From these new findings and the data reported in the previous papers, [3][4][5] we reasoned that this extraordinary activity could be ascribed to an interaction of the protonated amine substituent with a negatively charged site in the receptor. With the aim of finding if this putative "anionic site" really existed, we started a The EZ mixture is indicated where the amount of Z oxime is more than 10%.…”

Section: Introductionsupporting

confidence: 58%

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

et al. 2000

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A series of digitalis-like compounds with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the receptor, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na(+),K(+)-ATPase inhibitory potencies (IC(50)) 17-25 times higher than the standards digitoxigenin and digoxin and 3-11 times higher inotropic potencies (EC(50)) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 domains of Na(+),K(+)-ATPase. Some interactions are the classical ones already described in the literature; a new, very strong interaction of the basic group with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compounds were also studied in vivo in the anesthetized guinea pig for evaluating their inotropic effect versus the lethal dose. Compounds 9 and 12 showed a slightly higher safety ratio than digoxin and deserve further evaluation.

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Section: Introductionsupporting

confidence: 58%

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

et al. 2000

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“…Colchicine is used for treatment of gouty arthritis and Mediterranean fever; its toxic effect is related to tubuline depolymerization. Digoxin is a cardiotonic glycoside used to control ventricular rate in atrial fibrillation with a small margin between toxic and therapeutic doses; it acts on the Na+/K+ ATPase receptor [44]. Vincristine and vinblastine are anti-tumor microtubule modulators.…”

Section: Cell Viability and Animal Toxicitymentioning

confidence: 99%

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Guha

Schürer

2008

J Comput Aided Mol Des

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Computational toxicology is emerging as an encouraging alternative to experimental testing. The Molecular Libraries Screening Center Network (MLSCN) as part of the NIH Molecular Libraries Roadmap has recently started generating large and diverse screening datasets, which are publicly available in PubChem. In this report, we investigate various aspects of developing computational models to predict cell toxicity based on cell proliferation screening data generated in the MLSCN. By capturing feature-based information in those datasets, such predictive models would be useful in evaluating cell-based screening results in general (for example from reporter assays) and could be used as an aid to identify and eliminate potentially undesired compounds. Specifically we present the results of random forest ensemble models developed using different cell proliferation datasets and highlight protocols to take into account their extremely imbalanced nature. Depending on the nature of the datasets and the descriptors employed we were able to achieve percentage correct classification rates between 70% and 85% on the prediction set, though the accuracy rate dropped significantly when the models were applied to in vivo data. In this context we also compare the MLSCN cell proliferation results with animal acute toxicity data to investigate to what extent animal toxicity can be correlated and potentially predicted by proliferation results. Finally, we present a visualization technique that allows one to compare a new dataset to the training set of the models to decide whether the new dataset may be reliably predicted.

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“…13 In naturally occurring digitalis glycosides the unsaturated g-and d-lactones present in 17b-position of the steroidal skeleton are associated with high affinity for the Na þ /K þ -ATPase receptor. 15,16 Recently, it was confirmed that basicity, i.e. a strong ionic interaction between one of carboxylate residues present in the a-subunit of the Na þ /K þ -ATPase and the cationic form of some digitalis like derivatives is relevant for interference with enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Effects of Digoxin and Gitoxin on the Enzymatic Activity and Kinetic Parameters of Na⁺/K⁺-ATPase

Krstić

Krinulović

Spasojević-Tišma

et al. 2004

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibition of Na+/K+-ATPase activity from human erythrocyte membranes and commercial porcine cerebral cortex by in vitro single and simultaneous exposure to digoxin and gitoxin was investigated to elucidate the difference in the mechanism of the enzyme inhibition by structurally different cardiac glycosides. The drugs exerted a biphasic dose-dependent inhibitory effect on the enzyme activity in both tissues, supporting the existence of two sensitive Na+/K+-ATPase isoforms. The IC50 values for the low and high affinity isoforms were calculated from the inhibition curves using mathematical analysis. The Hill coefficient (n) fulfilled the relationship 1 < n < 3, suggesting cooperative binding of inhibitors to the enzyme. Kinetic analysis showed that digoxin and gitoxin inhibited Na+/K+-ATPase by reducing the maximum enzymatic velocity (Vmax) and Km, implying an uncompetitive mode of interaction. Both the isoforms were always more sensitive to gitoxin. The erythrocyte enzyme was more sensitive to the inhibitors in the range of low concentrations but the commercial cerebral cortex enzyme exerted a higher sensitivity in high inhibitors affinity concentration range. By simultaneous exposure of the enzyme to digoxin and gitoxin in combinations a synergistic effect was achieved by low inhibitor concentrations. An antagonistic effect was obtained with erythrocyte membrane enzyme at high inhibitors concentration.

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Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na⁺,K⁺-ATPase Receptor

Cited by 23 publications

References 15 publications

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Effects of Digoxin and Gitoxin on the Enzymatic Activity and Kinetic Parameters of Na⁺/K⁺-ATPase

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Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na+,K+-ATPase Receptor

Cited by 23 publications

References 15 publications

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na+,K+-ATPase Receptor

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na+,K+-ATPase Receptor

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Effects of Digoxin and Gitoxin on the Enzymatic Activity and Kinetic Parameters of Na+/K+-ATPase

Contact Info

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Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na⁺,K⁺-ATPase Receptor

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

Effects of Digoxin and Gitoxin on the Enzymatic Activity and Kinetic Parameters of Na⁺/K⁺-ATPase