title: 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.affiliation: 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.
authors.forename: Silmara L G
authors.initials: SLG
authors.lastname: Alves
authors.affiliation: 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.
authors.forename: Natasha
authors.initials: N
authors.lastname: Paixão
authors.affiliation: Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Letícia G R
authors.initials: LGR
authors.lastname: Ferreira
authors.affiliation: 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.
authors.forename: Felipe R S
authors.initials: FRS
authors.lastname: Santos
authors.affiliation: Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Luiza D R
authors.initials: LDR
authors.lastname: Neves
authors.affiliation: Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Gisele C
authors.initials: GC
authors.lastname: Oliveira
authors.affiliation: Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Cortes
authors.affiliation: Laboratório de RMN, Universidade Federal do Paraná, 81.531-990 Curitiba, PR, Brazil.
authors.forename: Kahlil S
authors.initials: KS
authors.lastname: Salomé
authors.affiliation: Laboratório de RMN, Universidade Federal do Paraná, 81.531-990 Curitiba, PR, Brazil.
authors.forename: Andersson
authors.initials: A
authors.lastname: Barison
authors.affiliation: Laboratório de Biologia Celular e Mutagenicidade, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Fabio V
authors.initials: FV
authors.lastname: Santos
authors.affiliation: Laboratório de Bioquímica de Parasitos, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Cenzi
authors.affiliation: Laboratório de Bioquímica de Parasitos, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Varotti
authors.affiliation: Laboratório de Bioinformática, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Soraya M F
authors.initials: SMF
authors.lastname: Oliveira
authors.affiliation: Laboratório de Bioinformática, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Taranto
authors.affiliation: Laboratório de Bioinformática, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Moacyr
authors.initials: M
authors.lastname: Comar
authors.affiliation: Laboratório de Biologia Celular e Inovação Biotecnológica, Fundação Ezequiel Dias, Rua Conde Pereira Carneiro 80, 305010-010 Belo Horizonte, Brazil.
authors.forename: Luciana M
authors.initials: LM
authors.lastname: Silva
authors.affiliation: 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.
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.affiliation: 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.
authors.forename: Luis Eduardo M
authors.initials: LEM
authors.lastname: Quintas
authors.affiliation: Laboratório de Bioquímica Celular, Universidade Federal de São João Del Rei, Campus Centro Oeste Dona Lindu, Divinópolis, MG 35501-296, Brazil.
authors.forename: Leandro A
authors.initials: LA
authors.lastname: Barbosa
authors.affiliation: 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.
authors.forename: José A F P
authors.initials: JAFP
authors.lastname: Villar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001597:Benzylidene Compounds / Q000737:chemistry*; D001665:Binding Sites; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004077:Digoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000201:enzymology; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Anticancer; Cancer; Cardiotonic steroids; Digoxin; Na,K-ATPase; γ-Benzylidene