RESUMO
We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.
Assuntos
Antineoplásicos Fitogênicos/biossíntese , Álcoois Graxos/metabolismo , Lactonas/metabolismo , Acetogeninas , Annona/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Transporte de Elétrons/efeitos dos fármacos , Álcoois Graxos/farmacologia , Furanos/farmacologia , Humanos , Ligação de Hidrogênio , Indicadores e Reagentes , Lactonas/farmacologia , Bicamadas Lipídicas , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Fosfatidilcolinas/química , Sementes/químicaRESUMO
The antitumoral activity of a series of acetylated bis-tetrahydrofuranic acetogenins with a threo/trans/threo/trans/erythro relative configuration was characterized by four new natural and two semisynthetic, 15,24,30-trioxygenated acetogenins that were found to inhibit mitochondrial complex I enzyme as well as growth of several tumor cell lines. Placement of acetyl groups along the alkyl chain modulated the potency of the bis-tetrahydrofuranic acetogenins and could be important for future utilization of these compounds as chemotherapeutic agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Álcoois Graxos/síntese química , Álcoois Graxos/farmacologia , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Acetogeninas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Álcoois Graxos/química , Inibidores do Crescimento/química , Humanos , Lactonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Annonaceous acetogenins are known to be cytotoxic against tumor cell lines by virtue of their inhibition of mitochondrial complex I. We decided to conclude part of our recent revisions of the different structure-activity relationships (SARs) found within these compounds with a detailed description of the cytotoxic activity, and correlations with the inhibition of the target enzyme, of the broadest subclass of this family of natural products, the bis-tetrahydrofuranic acetogenins (bis-THF ACGs) of threo/trans/threo/trans/erythro relative configuration. Five naturally occurring ACGs and more than 10 semisynthetic analogs were tested against the MCF-7 (breast), A-549 (lung), HepG2 (liver), HT-29 (colon), MES-SA (ovary), and a multidrug-resistant (MDR-MES-SA/Dx5) cell lines using the MTr cytotoxicity assay to determine if the mitochondrial complex I inhibition correlated with the in vitro antitumor potency of the most common ACGs. Results indicated that a previously observed trend for other subclasses of ACGs between the ED50 of the cytotoxicity assay and the polarity of compounds was not present in this set and that there were several specific interactions that enhanced the antitumor activity. For example, some of the guanacone derivatives prepared were two orders of magnitude more potent than the parent compound for specific cell lines.
Assuntos
Antineoplásicos Fitogênicos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Álcoois Graxos , Furanos , Lactonas , Mitocôndrias/efeitos dos fármacos , Acetogeninas , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Álcoois Graxos/síntese química , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Lactonas/síntese química , Lactonas/química , Lactonas/farmacologia , Mitocôndrias/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.