np9b01060_si_001.pdf (3.73 MB)
Na+/K+‑ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives
journal contribution
posted on 2020-02-25, 17:41 authored by Yulin Ren, Hennrique T. Ribas, Kimberly Heath, Sijin Wu, Jinhong Ren, Pratik Shriwas, Xiaozhuo Chen, Michael E. Johnson, Xiaolin Cheng, Joanna E. Burdette, A. Douglas Kinghorn(+)-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.