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

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: (+)-Digoxin ( 1) is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (2−5) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin ( 6) and (+)-17-epi-20,22-dihydro-21α-hydroxydigoxin (7), were synthesized from 1 and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure−activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for 1 to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic 1 and the noncytotoxic derivative 7 bind differentially to Na + /K + -ATPase. The HO-12β, HO-14β, and HO-3′aα hydroxy groups of (+)-digoxin (1) may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na + /K + -ATPase, respectively, but the altered lactone unit of 7 results in a rotation of its steroid core, which depotentiates the binding between this compound and Na + /K + -ATPase. Thus, 1 was found to inhibit Na + /K + -ATPase, but 7 did not. In addition, the cytotoxic 1 did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na + /K + -ATPase but not by interacting with glucose transporters.

Fungal Endophytes as Efficient Sources of Plant-Derived Bioactive Compounds and Their Prospective Applications in Natural Product Drug Discovery: Insights, Avenues, and Challenges

“…By stimulating the parasympathetic nerve, it slows electrical conduction in the AV node by increasing the refractory period of cardiac myocytes; therefore, it decreases the ventricular response and heart rate. Overall, the stroke volume is increased while the heart rate is decreased, resulting in a net increase in blood pressure [ 397 ]. Crude extracts of fungal cultures isolated from Digitalis lanata also showed the production of digoxin [ 382 ].…”

Na+/K+-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation

“…Another structural motif also significantly involved in the CS binding to NKA is the lactone at the C-17 position. Its derivatization usually leads to a reduction in the NKA inhibitory effects of the resulting derivative, both in the case of double bond saturation and cycle opening [ 138 , 139 ] as well as by the introduction of a benzylidene group at the C-21 position [ 140 , 141 ]. However, in some cases, this modification resulted in a change in the CS affinity for the individual NKA isoforms [ 142 ].…”

Quo vadis Cardiac Glycoside Research?

“…It is its saturation or opening of the whole cycle that results in a significant reduction in the inhibitory activity of the resulting ouabain derivative [ 68 ]. The presence of a hydroxyl group at the C-21 position in Dg also leads to a decrease in the inhibitory activity of the resulting derivative due to inappropriate rotation of the steroid skeleton at the NKA binding site [ 69 ]. However, other derivatives of Dg were also prepared and exhibited higher inhibitory activity compared to Dg and mainly enhanced selectivity for some NKA isoforms, which are in the case of the α-subunit four of them.…”