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

journal contribution
posted on 06.05.2022, 17:07 by Yulin Ren, Hennrique T Ribas, Kimberly Heath, Sijin Wu, Jinhong Ren, Pratik Shriwas, Xiaozhuo Chen, Michael JohnsonMichael Johnson, Xiaolin Cheng, Joanna BurdetteJoanna 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.

Funding

Discovery of Anticancer Agents of Diverse Natural Origin | Funder: NIH / NCI | Grant ID: P01 5P01CA125066-08

History

Citation

Ren, Y., Ribas, H. T., Heath, K., Wu, S., Ren, J., Shriwas, P., Chen, X., Johnson, M. E., Cheng, X., Burdette, J. E.Kinghorn, A. D. (2020). Na+/K+‑ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives. Journal of Natural Products, 83(3), 638-648. https://doi.org/10.1021/acs.jnatprod.9b01060

Publisher

American Chemical Society (ACS)

Language

en

issn

0163-3864