Open AccessNa+/K+-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives
Author(s) -
Yulin Ren,
H Taborda Ribas,
Kimberly Heath,
Sijin Wu,
Jinhong Ren,
Pratik Shriwas,
Xiaozhuo Chen,
Michael E. Johnson,
Xiaolin Cheng,
Joanna E. Burdette,
A. Douglas Kinghorn
Publication year - 2020
Publication title -
journal of natural products
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.976
H-Index - 139
eISSN - 1520-6025
pISSN - 0163-3864
DOI - 10.1021/acs.jnatprod.9b01060
Subject(s) - cytotoxicity , stereochemistry , chemistry , glycoside , digoxin , atpase , cardiac glycoside , lipophilicity , enzyme , ouabain , biochemistry , in vitro , sodium , heart failure , medicine , organic chemistry
(+)-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.