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  • 1
    ISSN: 1432-1912
    Keywords: Na+/K+-transporting ATPase ; Cardioactive steroids ; Structure-activity relationship ; Extrathermodynamic approach ; Lead structure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of the present study was to determine the lead structure in cardiac glycosides at the receptor level, i.e. the minimal structural requirement for specific and powerful receptor recognition. Accordingly 73 digitalis-like acting steroids were characterized as to the concentration effecting half-maximum inhibition of Na,K-ATPase from human cardiac muscle under standardized turnover conditions. Since the K i value equaled the apparent K D value, K′D was expressed in terms of the apparent standard Gibbs energy change ΔGo′ of steroid interaction with Na,K-ATPase. This allowed the use of the extrathermodynamic approach as a rational way of correlating in a quantitative manner, the potency and structure of the various steroidal compounds. The results of the present analysis taken in conjunction with relevant findings reported in the literature, favour the following conclusions. 1. Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis. 2. The butenolide ring of cardenolides or the analogous side-chains at C17β of 5β,14β-androstane-3β,14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead. 3. All modifications of the structure, geometry and spatial relationship between the steroid nucleus and butenolide side chain of digitoxigenin all at once weaken the close fit interaction with the steroid and butenolide binding subsites of the enzyme in such way that the cardenolide derivatives interact with the receptor binding site area in whatever orientation that will minimize the Gibbs energy of the steroid-receptor-solvent system. 4. The “butenolide carbonyl oxygen distance model” (Ahmed et al. 1983) for the interpretation of the differences in potency of the cardenolide derivatives describes the change in interaction energy through structural modification as a function of the entire molecule. 5. 5β,14β-androstane-3β,14-diol, the steroid nucleus of cardiac glycosides of the digitalis type, is the minimum structure for specific receptor recognition and the key structure for inducing protein conformational change and thus Na,K-ATPase inhibition. It is also the structural requirement for maximum contributions of the butenolide substituent at C17β and the sugar substituent at C3β-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure. 6. The tridigitoxose side-chain at C3β-OH of digitalis glycosides can be more than isoenergetically replaced by glucose, 2′,3′-O-isopropylidene-rhamnose, digitoxose, rhamnose and 4′-deoxy-4′-amino-rhamnose (increasing order of interaction energy increments) indicating a remarkable degree of conformational adaptability of the sugar binding subsite.
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  • 2
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The relationship between structure and circular dichroism was studied for a series of cardenolides including some compounds with saturated lactone ring.
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  • 3
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. I. α,β- and β,γ-Unsaturated Lactone Ring-Methylated CardenolidesBase-catalyzed methylation of digitoxigenin 1a with methyl iodide and sodium hydride in DMF leads to the α,β-unsaturated cardenolides 2-5 and, after rearrangement of the C=C-double bond, to the β,γ-unsaturated cardenolides 6 and 7. Opening of the lactone ring results in the formation of 8. Allylic oxidation of 4b affords the 14,21-epoxide 10. Only the 22-methyl derivative 4a and its 3-O-tridigitoxoside 4d show strong biological effectivity, whereas methylation at 21R- or 21S-position results in considerable loss in activity.
    Additional Material: 4 Tab.
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  • 4
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. II. Synthesis of Cardenolide-Analogous γ-Steroidyl-ButenolidesThe synthesis of the cardenolide-analogous stereoisomeric γ-steroidyl-butenolides 5 and 6 and of the γ-steroidyl-α-methyl-butenolide 13, starting from β-ketosulfoxide 3 by alkylation with methyl bromoacetate and methyl α-bromopropionate, respectively, followed by the sodium borohydride reduction of the alkylated intermediates is described. 1,3-dipolar addition of diazomethane to 5 followed by pyrolysis of butyrolactone-pyrazoline-adduct 11 yields γ-steroidyl-β-methyl-butenolide 10, the structural isomer of 13.
    Additional Material: 1 Tab.
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  • 5
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. III. Synthesis of Cardenolide-Analogous Methyl β-Steroidyl-crotonatesStarting with 14-hydroxy-5β, 14β-pregnan-3β-yl-acetate (2) the synthesis of the cardenolide analogues methyl 3β-acetoxy-14, 15β-epoxy-24-nor-5β, 14β-chol-20(22)-en-23-oate (7) via Reformatskij synthesis and methyl 3β, 14-dihydroxy-5β, 14β-chol-20(22)-en-23-oate (11) via addition of lithium ethoxyacetylide to 2 are described.The activity of 11 in the ATPase-test is about the same as that of digitoxigenin.
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  • 6
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Die Darstellung der isomeren Ring D-anellierten Steroidlactone 6 und 12 aus den 16-Acetoxy-17-ketosteroiden 1 bzw. 9 wird beschrieben. Der Verlauf der Äthinylierung zur Einführung der 17-ständigen α,β-ungesättigten Estergruppierung wird durch die Konfiguration an C-16 bestimmt:Die Umsetzung der 16β-Acetoxy-Verbindung führt zu dem erwarteten Äthoxyäthinylcarbinol 2b, das nach Desacetylierung in den α,β-ungesättigten 3β,14,16β-Trihydroxy-5β,14β-pregn-17(20)-en-21-säureäthylester 4 umgelagert wird. 4 wird in siedendem Eisessig direkt zum 3β-Acetoxy-14-hydroxy-5β,14β-pregn-17(20)-en-21,16β-lacton 6 cyclisiert.Aus der 16α-Acetoxy-Verbindung dagegen entsteht unmittelbar das 3β-Acetoxy-14,17-dihydroxy-5β,14β,17α-pregnan-21,16α-lacton 11, dessen 17β-OH-Gruppe unter Bildung des instabilen 3β-Acetoxy-14-hydroxy-5β,14β-pregn-17(20)-en-21,16α-lactons 12 eliminiert werden kann. 12 stabilisiert sich durch Verlagerung der Doppelbindung zum 3β-Acetoxy-14-hydroxy-5β,14β-pregn-16-en-21,16-lacton 13. Die anellierten Steroidlactone 6 und 13 erweisen sich bei der molekularbiologischen Wertbestimmung (ATPase-Test) als unwirksam.
    Additional Material: 2 Tab.
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  • 7
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. X. Synthesis of 22-O-Substituted Cardenolides and Studies on the Oxidative Degradation of Cardenolides with Potassium PermanganateThe stereoisomeric 20,22-dihydroxy-cardanolides 2a and 3a as well as the oxalic acid half ester of the 3β-acetoxy-14,21-dihydroxy-5β,14β-pregnan-20-one (4a) and 3β-acetoxy-20-oxo-5β,14β-pregnane-21,14-lactone (5) were identified as intermediates of oxidative degradation of digitoxigenin 3-acetate with potassium permanganate.2a and 3a, after selective acylation in 22-position, were converted to the 22-acyloxy-cardenolides 7a and 7b via dehydration or acetoxyelimination after selective acetylation of the 20-hydroxy group. Saponification of both 7a and 7b yields the very stable 22-hydroxy-cardenolide 8a.The molecular biological activities of the 22-substituted cardenolides were investigated and discussed.
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  • 8
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. XI. Synthesis of 3-(3β,14-Dihydroxy-5β,14β-androstan-17β-yl-methyl)but-2-en-4-olide, a Homologous 5β,14β-CardenolideWittig reaction of 3β,14-dihydroxy-5β,14β-androstane-17β-carboxaldehyde 4 with 2-carboxyl-1-ethoxycarbonyl-ethyl-triphenylphosphorane 11 followed by the reduction of the resulting half ester 5 and cyclization of the γ-hydroxy acid 6 yields the 3-alkylidenebutan-4-olide 8a which was isomerized to the 3-(steroidylmethyl)but-2-en-4-olide 9. Insertion of the methylene group between the steroidyl moiety and the but-2-en-4-olide ring strongly reduces the biological activity.Wegen der zentralen Bedeutung der relativen räumlichen Anordnung der 17β-ständigen Seitenkette zum Steroidgerüst für die positiv inotrope Wirkung der Herzsteroide wurden in den vergangenen Jahren umfangreiche partialsynthetische Arbeiten zur Herstellung von Cardenoliden und Cardenolid-Analogen mit dem Ziel einer veränderten geometrischen Anordnung des 17β-ständigen Lactonringes durchgeführt. Die Arbeiten konzentrierten sich vor allem auf die Einführung von Substituenten mit dem Ziel einer veränderten konformationellen Anordnung des 17β-ständigen Lactonringes [1-6] sowie auf eine veränderte Verknüpfung des Butenolidringes in α-Position (Actodigin) [7, 8] oder γ-Position [9] (anstelle β-Position bei den natürlich vorkommenden Cardenoliden) mit der 17β-Position des Steroidgerüstes. Die molekularbiologische Struktur-Wirkungsanalyse der bezeichneten Cardenolidderivate begünstigte den Schluß, daß für eine hohe Wirksamkeit der β-verknüpfte, unsubstituierte But-2-en-4-olidring und die in den Cardenoliden vorliegende räumliche Beziehung zwischen Butenolid-Seitenkette und Steroidgerüst erforderlich sind, durch die dann die komplementäre Geometrie von Seitenketten-Bindungsschlucht und Steroid-Bindungstasche (Erkennungsmatrix) im Rezeptorenzym, der (Na,K)-aktivierten Adenosintriphosphat-Phosphohydrolase (Na,K-ATPase) des Herzmuskels [10, 11], definiert ist [12].Für die Analyse der Grenzen zwischen fixierter Geometrie und induzierter Anpassung der Erkennungsmatrix gewannen die homologen Cardenolide hervorragendes Interesse, bei denen die Lacton-Seitenkette über eine Methylen- oder Methingruppe mit dem A/B-cis- und C/D-cis-konfigurierten Steroidgerüst verknüpft ist und dadurch Bezüglich Abstand und Winkel zum Steroidgerüst stark von deren relativer Orientierung in den natürlich vorkommenden, hochwirksamen Cardenoliden abweicht. Das von Güntert et al. [13] synthetisierte 4′-[(3β-Hydroxy-androst-5-en-17β-yl)methyl]-2′(5′H)-furanon, ein “17β-homologes 3β-Hydroxy-card-5,22-dienolid”, ist für die Beantwortung dieser Fragestellung nicht geeignet; wegen der trans-Verknüpfung anstelle der für eine Herzwirksamkeit zu fordernden cis-Verknüpfung der Ringe C und D konnte nach dem erreichten Erkenntnisstand über Struktur-Wirkungsbeziehungen [12, 14] eine fehlende Wirkung auf das Rezeptorenzym Na,K-ATPase und damit auf das insuffiziente Herz vorausgesagt werden.
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  • 9
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide-Analogues. XII. Synthesis of 21-Substituted Cardenolides by Oxidation of 17β - (3-Furyl)-Steroids and Nucleophilic SubstitutionOxidation of 17β-(3-furyl)-5β, 14β-androstane-3β, 14β-diol 3-acetate (2b) with chromic acid yielded the 14,21-epoxy-cardenolide 4. After elimination of the 14β-hydroxy group of 2b the unsaturated furyl derivative 5, when treated with chromic acid, gave a mixture of the diastereomeric unsaturated 21ξ-hydroxy-cardenolides 8a which were converted with N-bromoacetamide to a mixture of the 14β, 15β-epoxy-21ξ-hydroxy-cardenolides 9a.The hydroxy-cardenolides 8a and 9a were acetylated to the 21ξ-acetoxy-cardenolides 8b/8c and 9b/9c, respectively, and they reacted with primary and secondary amines to give the corresponding N-substituted 21ξ-amino-cardenolides 11a--11c and 12b, respectively. When reacted with p-toluenesulfonyl chloride both 8a and 9a yielded the 21ξ-chloro-cardenolides 11d/11e and 12c/12d, respectively, the chlorine of which could easily be substituted by SN1- and SN2-reactions.
    Additional Material: 1 Tab.
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  • 10
    ISSN: 0021-8383
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Partial Syntheses of Cardenolides and Cardenolide Analogues. XIII. Synthesis of Substituted 14,21-Epoxy-5β,14β-card-20(22)-enolideThe 12-substituted 14,21-epoxy-5β,14β-card-20(22)-enolides 3 and 5 were synthesized by oxidation of the appropriate 17β-(3-furyl) derivatives 2b and 2c, respectively, with chromic acid. 5 was converted to the conjugated Δ9(11)-12-ketone 6 by dehydrogenation with selenium dioxide.The biological activities of the new compounds were investigated and are discussed.
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