Chemical Models for the Chemical Nature of Endogenous Digitalis

Abstract

The inability or the capacity to promote the phosphorylation of Na+/K(+)-transporting ATPase (Na/K-ATPase) from [32P]Pi is shown to differentiate between mechanistically digitalis-unlike and digitalis-like inhibitors of this enzyme known to be the receptor for all digitalis actions. A negative or positive response in the phosphorylation promotion assay introduced here appears thus to be suitable to diagnose the chemical species in the isolates of animal origin related to the putative endogenous digitalis. Various digitalis-congeneric C/D-cis steroids, progesterone-congeneric C/D-trans steroids and the Erythrophleum alkaloid cassaine promote the enzyme phosphorylation and show a similar pattern of discrimination between three Na/K-ATPase variants. Thus, their cyclopentanoperhydrophenanthrene or perhydrophenanthrene nuclei appear to serve as the minimal pharmacophoric lead structures for bimolecular recognition and to represent chemical models for the chemical nature of endogenous digitalis. Specifically, the hormonal C/D-trans steroids could provide the basic skeleton in endogenous digitalis biosynthesis.

Apoptosis-mediated selective killing of malignant cells by cardiac steroids: maintenance of cytotoxicity and loss of cardiac activity of chemically modified derivatives

“…Although the chemically modified bufadienolide derivatives formally belong to the steroid group, they are lacking the basic structural requirements for glucocorticoid activity, namely the ketone group at C3, the D4,5 double bond, the ketol side chain at C17, and especially the hydroxyl group at C11 [38]. Moreover, in contrast to hormonal steroids, they all have a C/D cis-junction typical for cardiac steroids [39]. Therefore, the chemical changes which abrogated cardiac activity did not transform the substances into glucocorticoid hormones.…”

A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

“…Related to the stereochemistry of C/D rings junction, megestrol acetate and chlormadinol acetate (CMA), bearing C/D trans junction, inhibit Na + ,K + -ATPase [88]. CMA showed a potency similar to digitoxigenin in in vitro 3 H-ouabain binding assays.…”

“…Another argument is that cardiac glycosides do not produce hypertension at therapeutic doses. Some authors even speculate with certain C/D trans steroidal hormones as models for the chemical structure of endogenous digitalis [88]. They have also been proposed synthetic candidates as EDLF analogues [102].…”

A New Approach to the Design of Novel Inhibitors of Na+,K+-ATPase: 17α-Substituted Seco-D 5β-Androstane as Cassaine Analogues

“…1e,6 Its main chemical features are (a) a lipophilic perhydrophenanthrene nucleus; (b) the presence of an R,β-unsaturated ester moiety, a feature common to the 17β-substituents of classic cardioactive steroids; (c) a basic residue which is essential for its activity. 6 The importance of an ionic interaction in the region of the 17-substituent of Na + ,K + -ATPase inhibitors has been demonstrated by SAR studies also for digitalis-like compounds. 1a,5,7,8 In 1991, R. W. Baker et al 9 reported the synthesis of a series of cassaine analogues and demonstrated a significant contribution to the binding energy displayed by a hydrophobic interaction in the R region, approximately corresponding to the D-ring of digitalis compounds (C15-C16).…”