RESUMEN
Ten acetogenins, one of them new, were isolated from leaves and twigs of a Bolivian collection of Annona montana. The new compound that we named tucupentol (1) is a mono-tetrahydrofuran-pentahydroxy-acetogenin. The inhibitory potency of tucupentol (1) on the mitochondrial complex I was evaluated, and this activity was compared with that of the known acetogenins, annonacin-A, cis-annonacin-10-one, aromin, and gigantetronenin, also isolated from this plant material. The mentioned acetogenins acted as selective inhibitors of mitochondrial complex I in the 0.8-5.4-nM range.
Asunto(s)
Acetogeninas/aislamiento & purificación , Acetogeninas/farmacología , Annona/química , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Furanos/aislamiento & purificación , Furanos/farmacología , Animales , Bolivia , Bovinos , Concentración 50 Inhibidora , Mitocondrias Cardíacas/efectos de los fármacos , Resonancia Magnética Nuclear Biomolecular , Hojas de la Planta/química , Tallos de la Planta/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/biosíntesis , Alcoholes Grasos/metabolismo , Lactonas/metabolismo , Acetogeninas , Annona/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Simulación por Computador , Transporte de Electrón/efectos de los fármacos , Alcoholes Grasos/farmacología , Furanos/farmacología , Humanos , Enlace de Hidrógeno , Indicadores y Reactivos , Lactonas/farmacología , Membrana Dobles de Lípidos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Fosfatidilcolinas/química , Semillas/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Alcoholes Grasos/síntesis química , Alcoholes Grasos/farmacología , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Lactonas/síntesis química , Lactonas/farmacología , Acetogeninas , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejo I de Transporte de Electrón/metabolismo , Alcoholes Grasos/química , Inhibidores de Crecimiento/química , Humanos , Lactonas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Alcoholes Grasos , Furanos , Lactonas , Mitocondrias/efectos de los fármacos , Acetogeninas , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Bovinos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Alcoholes Grasos/síntesis química , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Furanos/síntesis química , Furanos/química , Furanos/farmacología , Humanos , Lactonas/síntesis química , Lactonas/química , Lactonas/farmacología , Mitocondrias/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new beta-hydroxy-gamma-methyl-gamma-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin)was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex I in the 0.18 - 1.55 nM range.
Asunto(s)
Annona , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Furanos/farmacología , Lactonas/farmacología , Fitoterapia , Extractos Vegetales/farmacología , Complejo I de Transporte de Electrón/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Furanos/administración & dosificación , Furanos/uso terapéutico , Humanos , Concentración 50 Inhibidora , Lactonas/administración & dosificación , Lactonas/uso terapéutico , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/enzimología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , SemillasRESUMEN
Four bisbenzyltetrahydroisoquinoline alkaloids (-)-medelline, (+)-antioquine, (+)-aromoline, and (+)-obamegine were isolated from the fruits of Xylopia columbiana. These compounds, the previously isolated alkaloids (+)-thaligrisine and (+)-isotetrandrine, as well as their O-acetylated derivatives were assayed on submitochondrial particles from beef heart as inhibitors of the mammalian respiratory chain. The results revealed that these alkaloids act as selective inhibitors of mitochondrial complex I in a 0.15 - 4.71 microM range. O-Acetylation, which increases their lipophilicity, considerably increased the inhibitory potency.
Asunto(s)
Annonaceae , Bencilisoquinolinas/farmacología , Inhibidores Enzimáticos/farmacología , NADH NADPH Oxidorreductasas/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Animales , Bencilisoquinolinas/administración & dosificación , Bencilisoquinolinas/uso terapéutico , Bovinos , Transporte de Electrón/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Concentración 50 Inhibidora , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/biosíntesis , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéuticoRESUMEN
Modifications in the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety or in the alkyl chain that links this terminal gamma-lactone with the alpha,alpha'-dihydroxylated THF system of the natural mono-tetrahydrofuranic acetogenins, annonacin and annonacinone, led to the preparation of eight semisynthetic derivatives. Their inhibitory effects on mitochondrial complex I is discussed and compared with that of the classical complex I inhibitor, rotenone.
Asunto(s)
Complejo I de Transporte de Electrón/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Alcoholes Grasos/síntesis química , Alcoholes Grasos/farmacología , Lactonas/síntesis química , Lactonas/farmacología , Acetogeninas , Furanos/síntesis química , Furanos/farmacología , Cinética , Complejos Multienzimáticos/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidoresRESUMEN
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.