Cardiac Glycosides. 4. A Structural and Biological Analysis of β-d-Digitoxosides, β-d-Digitoxose Acetonides, and Their Genins

Douglas C. Rohrer, Masaru Kihara, Tamboue Deffo, Hargovind Rathore, Khalil Ahmed, Arthur H.L. From, Dwight S. Fullerton

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14 Scopus citations


The structural and conformational characteristics of a series of five cardenolide analogues, their digitoxose acetonide derivatives, and their digitoxoside derivatives are determined from analysis of crystal structure results (including seven new structures reported here) and molecular mechanics calculations. The A, B, and C rings in the steroid backbone remain essentially conformationally invariant in all the structures, while the D rings show a high degree of flexibility. The conformational characteristics of the C17β side groups on the various analogues do not seem to be significantly affected by the nature of the C3 substituent. The bonds linking the steroid to the sugar moieties show a surprisingly small range of rotational freedom. The C2′-Cl′-O3-C3 torsion angles range only over 29.4° in 10 crystal structures, while the Cl′-O3-C3-C2 torsion angles range over 110.1°. A comparison of the structural characteristics of the “active” conformations of theses analogues and their derivatives with their potency as hog kidney Na+,K+-ATPase inhibitors reveals that the same type of linear relationship observed earlier for the genins exists for the glycoside derivatives. However, the addition of the sugar substituent enhances the potency in a specific way. The potencies of the digitoxose acetonide derivatives with the C3′ and C4′ oxygens blocked are increased systematically by a factor of 2, while the digitoxoside derivatives with free hydroxyls at C3′ and C4′ show a systematic potency enhancement of a factor of 10. These results are consistent with either O3′ or O4′ being involved in the enhancing process, but other earlier work indicates that the orientation of O4′ has the predominant influence.

Original languageEnglish (US)
Pages (from-to)8269-8276
Number of pages8
JournalJournal of the American Chemical Society
Issue number26
StatePublished - Dec 1 1984


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