RESUMEN
The isolation and structural elucidation of a new naphthylisoquinoline alkaloid, 8-O-methyldioncophyllinol B, from Triphyophyllum peltatum (Hutch. et Dalz.) Airy Shaw (Dioncophyllaceae) is described, together with the revised structures of other 'B-type' compounds previously misidentified as dioncophylline D, dioncophyllinol D, and 8-O-methyldioncophylline D. All of the presently described structures are 7,6'-coupled and thus have to be addressed as 'B-type' naphthylisoquinoline alkaloids. This is in contrast to the initially defined 'D-type' structures, which are 7,8'-coupled as confirmed by a total synthesis of dioncophylline D. Some of these natural and synthetic naphthylisoquinolines were found to display good in vitro antiplasmodial activities.
Asunto(s)
Alcaloides/química , Isoquinolinas/química , Naftoles/química , Plantas Medicinales/química , Alcaloides/aislamiento & purificación , Cromatografía de Gases y Espectrometría de Masas , Isoquinolinas/aislamiento & purificación , Modelos Moleculares , Conformación Molecular , Naftoles/aislamiento & purificación , Hojas de la Planta/químicaRESUMEN
The growth and droserone content of callus cultures of Triphyophyllum peltatum grown in liquid 1/5 Linsmaier and Skoog medium was studied. During a lag phase in growth, droserone concentrations in the medium reached a value of 2.1 mg g-1 fr. wt. After this maximum value the concentration decreased slightly to 1.8 mg g-1 fr. wt., while the growth of the calli was enhanced (25% increase in fr. wt. within 7 days). Plumbagin and isoshinanolone were likewise present in the medium. By feeding 13C2-labelled acetate to the cultures the biosynthesis of droserone was elucidated. The incorporation of whole C2-units unambiguously shows its acetogenic origin and fits well in the biosynthetic scheme suggested for the structurally--and biogenetically--related naphthylisoquinoline alkaloids.
Asunto(s)
Naftoquinonas/aislamiento & purificación , Plantas/metabolismo , Células Cultivadas , Naftoquinonas/química , Naftoquinonas/metabolismo , Células VegetalesRESUMEN
Natural and synthetic anthranoid compounds were subjected to an evaluation against asexual erythrocytic stages of the human malaria parasite Plasmodium falciparum in vitro. Stimulated by the good activities of Vismia guineënsis extracts, a more detailed investigation of the active principles revealed the pre-nylated preanthraquinone vismione H (1) to be a potent antimalarial [50% growth-inhibitory concentration (IC50) 0.088 microg/ml]. On the basis of this finding a series of chemically related phlegmacins (2-5), flavomannins (6-8), and rufoolivacins (9-11) isolated from several species of Cortinarius, a genus of higher fungi, and 5 synthetic vismione-like anthranoids (12-16) were evaluated as well. Although these compounds displayed weaker antiplasmodial effects than did vismione H (1) itself, considerable levels of activity were obtained with phlegmacin B1 (2), flavomannin-6,6'-di-O-methyl ether A1 (6), trans-4-hydroxy-flavomannin-6,6'-di-O-methyl ether A (8), and rufoolivacin B (10). Initial preconditions for activity within the vismiones and related anthranoids were established.
Asunto(s)
Antracenos/farmacología , Antimaláricos/farmacología , Extractos Vegetales/farmacología , Plasmodium falciparum/efectos de los fármacos , Agaricales/metabolismo , Animales , Antracenos/síntesis química , Antracenos/química , Antimaláricos/síntesis química , Antimaláricos/química , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Humanos , Extractos Vegetales/química , Relación Estructura-ActividadRESUMEN
Hannoa chlorantha and Hannoa klaineana (Simaroubaceae) are used in traditional medicine of Central African countries against fevers and malaria. Four stem bark extracts from H. klaineana and four quassinoids from H. chlorantha were examined in vitro against Plasmodium falciparum NF 54. The extracts displayed good activities, while the quassinoids were highly active, with IC50 values well below 1 microgram ml-1, those of chaparrinone and 15-desacetylundulatone being much lower than 0.1 microgram ml-1 (0.037 and 0.047 microgram ml-1, respectively). Chaparrinone is five times more active than 14-hydroxychaparrinone against P. falciparum, indicating that the hydroxyl function at C-14 is unfavourable for antiplasmodial activity. As 14-hydroxychaparrinone has a seven-times higher cytotoxic activity against P-388 cells than chaparrinone, the latter compound has the better antiplasmodial therapeutic index. All four quassinoids were evaluated in vivo in a standard 4-day test as well. 15-Desacetylundulatone was proven to be the most active compound, almost totally suppressing the parasitaemias of OF1 mice for at least 7 days, while both chaparrinone and 14-hydroxychaparrinone were active for at least 4 days. Quassinoids have ED50 values much lower than 50 mg kg-1 body weight day-1 and none of them caused obvious side effects. The keto function at C-2 in 15-desacetylundulatone is apparently of crucial importance for its high activity. 6-alpha-Tigloyloxyglaucarubol was not active at all. Chaparrinone is considered the most interesting of the investigated quassinoids and its in-vivo antimalarial potential will be examined further.
Asunto(s)
Antimaláricos/farmacología , Malaria/tratamiento farmacológico , Extractos Vegetales/farmacología , Plantas Medicinales , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Cuassinas , Animales , Antimaláricos/química , Antimaláricos/toxicidad , Supervivencia Celular/efectos de los fármacos , Femenino , Glaucarrubina/análogos & derivados , Glaucarrubina/química , Glaucarrubina/farmacología , Glaucarrubina/toxicidad , Leucemia P388 , Ratones , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Raíces de Plantas/química , Plantas Medicinales/química , Semillas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Peroxidase active preparations from three Ancistrocladus species and from Triphyophyllum peltatum have been partially purified. They catalyze the oxidative dimerization of korupensamines A and B to michellamines A and C, respectively, as well as the mixed coupling to michellamines A, B, and C. All of these enzymes consist of single polypeptides of approximately 65 kDa with peroxidase activity as monomers. They were characterized as soluble proteins predominantly localized in the leaf phloem of all species examined. Comparative studies with various naphthol precursors revealed an unexpected substrate specificity. Only korupensamines were dimerized by the enzymes, while other monomers, even if closely related, were not accepted as substrates. The coupling reactions described here represent the first direct synthesis of michellamines from korupensamines without previous protection of these precursors.
Asunto(s)
Alcaloides/metabolismo , Fármacos Anti-VIH/metabolismo , Isoquinolinas/metabolismo , Magnoliopsida/enzimología , Naftalenos/metabolismo , Peroxidasas/metabolismo , Oxidación-Reducción , Especificidad de la Especie , Distribución TisularRESUMEN
Naphthylisoquinoline alkaloid-containing extracts from species of the families Dioncophyllaceae and Ancistrocladaceae and purified alkaloids derived therefrom were shown to exhibit antiparasitic activity in Plasmodium berghei-infected mice. Several extracts and alkaloids, especially dioncophylline C and dioncopeltine A, isolated from Triphyophyllum peltatum (Dioncophyllaceae), displayed high levels of activity. Dioncopeltine A was able to suppress parasitemia almost totally, while dioncophylline C cured infected mice completely after oral treatment with 50 mg kg of body weight(-1) day(-1) for 4 days without noticeable toxic effects. Analysis of the dose-response relationship of dioncophylline C revealed a 50% effective dosage (ED50) of 10.71 mg kg(-1) day(-1) under these conditions. Although four daily treatments with 50 mg kg(-1) day(-1) are needed to achieve radical cure, one oral dose is sufficient to kill 99.6% of the parasites. Intravenous application of dioncophylline C is even more effective, with an ED50 of 1.90 mg kg(-1) day(-1) and no noticeable toxic effects. The compound also suppressed more established P. berghei infections when orally applied at day 3 after infection. Both dioncopeltine A and dioncophylline C are active against the chloroquine-resistant P. berghei Anka CRS parasites. Sustained release of these compounds at 20 mg kg(-1) day(-1) by implanted miniosmotic pumps exhibited curative effects. The naphthylisoquinoline alkaloids are therefore promising new antimalarial agents.
Asunto(s)
Antimaláricos/uso terapéutico , Isoquinolinas/uso terapéutico , Malaria/tratamiento farmacológico , Naftoles/uso terapéutico , Plasmodium berghei , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Plasmodium berghei/efectos de los fármacosRESUMEN
The known lupane-type triterpene betulinic acid (3) was isolated for the first time from Triphyophyllum peltatum and Ancistrocladus heyneanus. It was found to exhibit moderate to good in vitro antimalarial activity against asexual erythrocytic stages of the human malaria parasite Plasmodium falciparum. A first X-ray structure analysis succeeded after conversion into its benzyl ester 4.
Asunto(s)
Antimaláricos/aislamiento & purificación , Plantas Medicinales , Plasmodium falciparum/efectos de los fármacos , Triterpenos/aislamiento & purificación , Animales , Antimaláricos/química , Antimaláricos/toxicidad , Cristalografía por Rayos X , Eritrocitos/parasitología , Humanos , Modelos Moleculares , Estructura Molecular , Triterpenos Pentacíclicos , Triterpenos/química , Triterpenos/toxicidad , Ácido BetulínicoRESUMEN
Naphthylisoquinoline alkaloids are derived from Dioncophyllaceae and Ancistrocladaceae species and comprise a new class of promising antimalarials with a demonstrated potential against asexual erythrocytic Plasmodium falciparum and P. berghei stages in vitro. We report herein the pronounced activity of pure naphthylisoquinoline alkaloids against exoerythrocytic malaria parasites. P. berghei-infected human hepatoma cells (Hep G2) were incubated with culture medium containing selected alkaloids at 10 micrograms/ml. The most active compounds, showing inhibitory activity of more than 40%, were dioncophylline A (compound 1), dioncophyllacine A (compound 6), and ancistrobarterine A (compound 12). For structure-activity investigations of dioncophyllines A (compound 1) and C (compound 3) and ancistrocladine (compound 7) a selection of their analogs from natural or synthetic sources was examined. Dioncophylline A (compound 16), 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (compound 17), N-formyl-8-O-methyl-dioncophylline C (compound 21), and N-formyl-8-O-benzoyldioncophylline C (compound 24) were found to display high levels of activity as well, although the former two compounds caused damage to the host-cell monolayers. As naphthylisoquinoline alkaloids are also highly active against blood forms of Plasmodium spp., they should be regarded as lead compounds for further development as drugs against erythrocytic and exoerythrocytic stages of Plasmodium spp.
Asunto(s)
Antimaláricos/farmacología , Isoquinolinas/farmacología , Naftoles/farmacología , Plasmodium berghei/efectos de los fármacos , Tetrahidroisoquinolinas , Alcaloides/farmacología , Animales , Células Cultivadas , Humanos , Plasmodium berghei/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
The naphthylisoquinoline alkaloids dioncophylline A (1) and 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (2) represent a new structural type of molluscicidal compounds and the active principle of extracts of the tropical lianas Ancistrocladus abbreviates and Triphyophyllum peltatum. The activity of 1 was further improved by derivatization.