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
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
Annonaceous acetogenins (ACG) are a large family of natural products that have been described as the most potent in vitro inhibitors of the mitochondrial respiratory chain Complex I. During the last two decades a large number of related structures have been discovered, increasing the number of members of this family. The large diversity of structural moieties and the general trends observed for inhibiting both growth of tumor cell lines and mitochondrial respiratory chain activity have resulted in the classification of these compounds into several structural groups according to their potency. Among them, the adjacent bis-tetrahydrofuranic acetogenins (bis-THF ACG) with a threo/cis/threo/cis/erythro relative configuration, have been described as the most potent subgroup, the prototypical member of which, rolliniastatin-1, was originally isolated from Rollinia membaranacea seeds. In this report we describe the different structure-activity relationships (SAR) observed for some natural ACG and semisynthetic derivatives as growth inhibitors of human tumor breast, lung, liver, and colon cell lines. All the compounds assayed showed potencies in the micromolar range. Trends observed in the cytotoxicity assay have been compared with previous data reported for these compounds as inhibitors of mitochondrial respiratory chain.