Identification and characterization of novel sodium/potassium-ATPase inhibitors by virtual screening of a compound database

Na+/K+-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives

“…It has been reported previously that (+)-digoxin ( 1 ) inhibits potently Na + /K + -ATPase activity, and the substituents at C-10, C-12, and C-17 of the steroid core of 1 or other cardiac glycosides could affect critically this enzyme inhibitory effect . Thus, the cytotoxic (+)-digoxin ( 1 ) and its noncytotoxic analogue, (+)-17- epi -20,22-dihydro-21α-hydroxydigoxin ( 7 ), were tested for their ability to inhibit Na + /K + -ATPase activity herein.…”

“…It has been reported previously that (+)-digoxin (1) inhibits potently Na + /K + -ATPase activity, 42 and the substituents at C-10, C-12, and C-17 of the steroid core of 1 or other cardiac glycosides could affect critically this enzyme inhibitory effect. 43 Thus, the cytotoxic (+)-digoxin (1) and its noncytotoxic analogue, (+)-17-epi-20,22-dihydro-21α-hydroxydigoxin (7), were tested for their ability to inhibit Na + /K + -ATPase activity herein. The cellular enzyme adenosine 5′-triphosphatase from the porcine cerebral cortex was treated with various concentrations of both cardiac glycosides, and, as expected, 1 inhibited Na + /K + -ATPase activity in a concentration-dependent manner, with an IC 50 value of 0.23 μM (Figure 2C), but 7 did not at concentrations less than 100 μM (IC 50 160.2 μM) (Figure 2D), indicating that the cytotoxicity of 1 could result from its Na + /K + -ATPase inhibitory activity.…”

Quantitative Structure–Activity Relationship Studies on Na+,K+-ATPase Inhibitors

“…71 The primary instance of a nine-membered chain (a−i) occurs in the C and D rings of the steroidal nucleus and an additional occurrence of such a nine-membered chain (j−r) can also be observed in some compounds such as 11. Another important feature for the activity of cardiac glycosides indicated by Stanton et al 69 as well as Paula et al 72 is the cis−trans stereochemistry of bonds C5−C10 and C13−C14, connecting rings A and B and C and D, respectively. A cis fusion of the rings at either or both the bonds can be more favorable to the activity than the transfusion.…”

“…These authors proposed that binding of cardiac glycoside occurs in two steps: first binding of the steroid and then a slower interaction of the sugar residues. 67,68 In a recent study, Stanton et al 69 reported that the nature of substituent at the 17β-position is an important determinant of the activity. In most active glycosides, it is a monounsaturated five-membered furanone.…”

“…Stanton et al 69 also performed a partial least-squares (PLS) regression analysis on a set of cardiac glycosides. The PLS regression analysis, also known as projection to latent structures technique, is an alternative approach to the linear multiple regression analysis (Hansch approach) fitted by least-squares, if the number of independent variables (descriptors) is relatively high compared with the number of data points (number of compounds in a given series) and several of the independent variables are mutually correlated.…”