γ-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect.

Abstract

Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.

• Authors: Silmara L G Alves, Natasha Paixão, Letícia G R Ferreira, Felipe R S Santos, Luiza D R Neves, Gisele C Oliveira, Vanessa F Cortes, Kahlil S Salomé, Andersson Barison, Fabio V Santos, Gisele Cenzi, Fernando P Varotti, Soraya M F Oliveira, Alex G Taranto, Moacyr Comar, Luciana M Silva, François Noël, Luis Eduardo M Quintas, Leandro A Barbosa, José A F P Villar
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 4397-4404 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26122772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzylidene Compounds
• Digoxin
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Benzylidene Compounds (chemistry)
• Binding Sites
• Brain (enzymology)
• Cell Line
• Cell Survival (drug effects)
• Digoxin (analogs & derivatives, chemical synthesis, toxicity)
• HeLa Cells
• Humans
• Kidney (enzymology)
• Molecular Docking Simulation
• Protein Structure, Tertiary
• Rats
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors, metabolism)