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

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

  • Bioorg Med Chem. 2015 Aug 1;23(15):4397-4404. doi: 10.1016/j.bmc.2015.06.028.
Silmara L G Alves 1,  Natasha Paixão 2,  Letícia G R Ferreira 3,  Felipe R S Santos 1,  Luiza D R Neves 3,  Gisele C Oliveira 3,  Vanessa F Cortes 3,  Kahlil S Salomé 4,  Andersson Barison 4,  Fabio V Santos 5,  Gisele Cenzi 6,  Fernando P Varotti 6,  Soraya M F Oliveira 7,  Alex G Taranto 7,  Moacyr Comar 7,  Luciana M Silva 8,  François Noël 2,  Luis Eduardo M Quintas 2,  Leandro A Barbosa 3,  José A F P Villar 9
Affiliations

Affiliations

  • 1 Laboratório de Síntese Orgânica e NanoEstruturas, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Av Sebastião Gonçalves Coelho, 400, Bairro Chanadour, Divinópolis, MG CEP 35501-296, Brazil.
  • 2 Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av Carlos Chagas, 373, 21941-902 Rio de Janeiro, Brazil.
  • 3 Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
  • 4 Laboratório de RMN, Universidade Federal do Paraná, 81.531-990 Curitiba, PR, Brazil.
  • 5 Laboratório de Biologia Celular e Mutagenicidade, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
  • 6 Laboratório de Bioquímica de Parasitos, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
  • 7 Laboratório de Bioinformática, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
  • 8 Laboratório de Biologia Celular e Inovação Biotecnológica, Fundação Ezequiel Dias, Rua Conde Pereira Carneiro 80, 305010-010 Belo Horizonte, Brazil.
  • 9 Laboratório de Síntese Orgânica e NanoEstruturas, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Av Sebastião Gonçalves Coelho, 400, Bairro Chanadour, Divinópolis, MG CEP 35501-296, Brazil. Electronic address: zevillar@ufsj.edu.br.
PMID: 26122772 DOI: 10.1016/j.bmc.2015.06.028
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.

Keywords

Anticancer; Cancer; Cardiotonic steroids; Digoxin; Na,K-ATPase; γ-Benzylidene.

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