RESUMEN
A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 µM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).
Asunto(s)
Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Poríferos/química , Pirroliminoquinonas/aislamiento & purificación , Pirroliminoquinonas/farmacología , Animales , Antimaláricos/metabolismo , Antimaláricos/toxicidad , Línea Celular , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Plasmodium falciparum/efectos de los fármacos , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/toxicidadRESUMEN
A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the identification of a new bromotyrosine alkaloid, psammaplysin G (1), along with the previously isolated compound, psammaplysin F (2). When tested against two different strains of the parasite Plasmodium falciparum (Dd2 and 3D7), 2 displayed IC(50) values of 1.4 and 0.87 microM, respectively, while 1 showed 98% inhibition at 40 microM against the chloroquine-resistant (Dd2) strain of P. falciparum.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Hidrocarburos Bromados/aislamiento & purificación , Hidrocarburos Bromados/farmacología , Plasmodium falciparum/efectos de los fármacos , Poríferos/química , Tirosina/análogos & derivados , Alcaloides/química , Animales , Antimaláricos/química , Australia , Cloroquina/farmacología , Relación Dosis-Respuesta a Droga , Hidrocarburos Bromados/química , Biología Marina , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Tirosina/química , Tirosina/aislamiento & purificación , Tirosina/farmacologíaRESUMEN
Mass-directed isolation of the CH(2)Cl(2)/MeOH extract of Doryphora sassafras resulted in the purification of a new benzylisoquinoline alkaloid, 1-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methylisoquinolinium trifluoroacetate (1), and the known aporphine alkaloid (S)-isocorydine (2). The structures of 1 and 2 were determined by 1D and 2D NMR and MS data analyses. The compounds were isolated during a drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 1 displayed IC(50) values of 3.0 and 4.4 microM, respectively. Compound 1 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and displayed no activity at 120 microM.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Bencilisoquinolinas/aislamiento & purificación , Bencilisoquinolinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Alcaloides/química , Animales , Antimaláricos/química , Australia , Bencilisoquinolinas/química , Ecosistema , Humanos , Estructura Molecular , Pruebas de Sensibilidad ParasitariaRESUMEN
Three new marine alkaloids, clavatadines C-E (1-3), together with the three known compounds aerophobin 1 (4), purealdin L (5), and aplysinamisine II (6) were isolated from extracts of the sponge Suberea clavata by bioassay-guided fractionation using a serine protease factor XIa assay. Their structures were determined by 1D and 2D NMR spectroscopy. Compounds 1-6 exhibited weak inhibition of factor XIa.
Asunto(s)
Alcaloides/aislamiento & purificación , Guanidinas/aislamiento & purificación , Poríferos/química , Alcaloides/química , Alcaloides/farmacología , Animales , Australia , Factor XIa/antagonistas & inhibidores , Guanidinas/química , Guanidinas/farmacología , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
With the aim of finding new natural product antimalarials, the novel indole alkaloids flinderole A-C were found to have selective antimalarial activities with IC(50) values between 0.15-1.42 microM. Flinderole A was isolated from the Australian plant Flindersia acuminata and flinderoles B and C from the Papua New Guinean plant F. amboinensis. Flinderoles A-C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds.
Asunto(s)
Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Rutaceae/química , Animales , Antimaláricos/química , Evaluación Preclínica de Medicamentos , Alcaloides Indólicos/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Parásitos/efectos de los fármacos , Parásitos/crecimiento & desarrolloRESUMEN
Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.
Asunto(s)
Productos Biológicos/aislamiento & purificación , Inhibidores del Factor Xa , Fibrinolíticos/aislamiento & purificación , Guanidinas/aislamiento & purificación , Fenilacetatos/aislamiento & purificación , Poríferos/química , Animales , Productos Biológicos/química , Fraccionamiento Químico , Cristalografía por Rayos X , Factor Xa/química , Fibrinolíticos/química , Guanidinas/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Fenilacetatos/químicaRESUMEN
Isoprenylcysteine carboxyl methyltransferase (Icmt) is enzyme target in anticancer drug discovery. An Icmt natural product high-throughput screening campaign was conducted and a hit extract from the roots of Hovea parvicalyx was identified. 2'-Methoxy-3'-prenyl-licodione and 2'-methoxy-3',3''-diprenyl-licodione, two prenylated beta-hydroxychalcone compounds, together with the known flavanone (S)-glabrol, were isolated and identified as bioactive constituents. Their structures were determined largely by 1D and 2D NMR spectroscopy.
Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/química , Fabaceae/química , Proteína Metiltransferasas/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética , Estructura Molecular , Proteína Metiltransferasas/metabolismoRESUMEN
The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening campaign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.
Asunto(s)
Poríferos/química , Proteína Metiltransferasas/antagonistas & inhibidores , Tirosina/análogos & derivados , Animales , Australia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Tirosina/química , Tirosina/aislamiento & purificación , Tirosina/farmacologíaRESUMEN
A new natural product, lysianadioic acid, was isolated from the plant Lysiana subfalcata as a carboxypeptidase B (CPB) inhibitor. It is a potent inhibitor of CPB with an IC(50) of 0.36 microM. This is the first known example of a small molecule CPB inhibitor isolated from plant origin. Its structure was determined by NMR spectroscopy.
Asunto(s)
Arginina/análogos & derivados , Carboxipeptidasa B/antagonistas & inhibidores , Guanidinas/química , Guanidinas/farmacología , Loranthaceae/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Succinatos/química , Succinatos/farmacología , Guanidinas/aislamiento & purificación , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Inhibidores de Proteasas/aislamiento & purificación , Succinatos/aislamiento & purificaciónRESUMEN
As part of our studies to discover P2X 7 receptor antagonists, the sponge Callyspongia sp. was investigated. A new tripyridine alkaloid niphatoxin C ( 1) was isolated and had P2X 7 receptor antagonism; however, cytotoxicity of THP-1 cells was the predominant biological effect at higher concentrations. Its structure was determined by 1- and 2-D NMR spectroscopy.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Callyspongia/química , Antagonistas del Receptor Purinérgico P2 , Compuestos de Piridinio/aislamiento & purificación , Compuestos de Piridinio/farmacología , Alcaloides/sangre , Alcaloides/química , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Monocitos/efectos de los fármacos , Compuestos de Piridinio/sangre , Compuestos de Piridinio/química , Receptores Purinérgicos P2X7RESUMEN
The sponge Psammoclemma sp. was investigated as part of our studies to discover P2X 7 receptor antagonists for the treatment of inflammatory disease. The biological activity of this extract was found to be due to the cytotoxicity of two new bromotyrosine alkaloids, psammaplysenes C (1) and D (2), and not P2X 7-specific activity. Their structures were determined by 1D and 2D NMR spectroscopy.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Citotoxinas/aislamiento & purificación , Citotoxinas/farmacología , Poríferos/química , Antagonistas del Receptor Purinérgico P2 , Tirosina/análogos & derivados , Alcaloides/química , Animales , Australia , Citotoxinas/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Receptores Purinérgicos P2X7 , Tirosina/química , Tirosina/aislamiento & purificación , Tirosina/farmacologíaRESUMEN
Isoprenylcysteine methyltransferase (Icmt) catalyzes the carboxyl methylation of oncogenic proteins in the final step of a series of post-translational modifications. The inhibition of Icmt provides an attractive and novel anticancer target. A natural product high-throughput screening campaign was conducted to discover inhibitors of Icmt. The Australian marine sponge, Pseudoceratina sp., yielded spermatinamine, a novel alkaloid with a bromotyrosyl-spermine-bromotyrosyl sequence, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy. Spermatinamine is the first natural product inhibitor of Icmt.
Asunto(s)
Antineoplásicos/toxicidad , Productos Biológicos/química , Productos Biológicos/toxicidad , Neoplasias/enzimología , Proteína Metiltransferasas/antagonistas & inhibidores , Espermina/análogos & derivados , Tirosina/análogos & derivados , Antineoplásicos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Espectroscopía de Resonancia Magnética , Estructura Molecular , Neoplasias/patología , Proteína Metiltransferasas/metabolismo , Espermina/química , Espermina/toxicidad , Tirosina/química , Tirosina/toxicidadRESUMEN
A new chlorotryptamine alkaloid, N-chloromethyl-N,N-dimethyltryptamine, was isolated from a methanol extract of the Chinese shrub Acacia confusa Merr., together with its known hallucinogenic analogues, N-methyltryptamine, N,N-dimethyltryptamine and N,N-dimethyltryptamine-N-oxide. The new compound was an artefact of the isolation conditions. The complete (1)H and (13)C NMR assignments for these compounds were carried out using (1)H, (13)C, DEPT, gCOSY, gHSQC and gHMBC NMR experiments.
Asunto(s)
Acacia/química , Alcaloides/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Resonancia Magnética Nuclear Biomolecular , Triptaminas/aislamiento & purificación , Metanol/química , Estructura MolecularRESUMEN
The distribution of the P2X7 receptor in inflammatory cells suggests that P2X7 antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening campaign to discover P2X7 receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC50 0.7 microM) and B (IC50 1.8 microM), as the specific bioactive constituents. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity in the hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the known pyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecific activity. ROESY and proton coupling constant data indicated that the stereochemistry at C12, C17, and C20 in 4,5-dibromopalau'amine should be revised to 12R, 17S, 20S. By analogy, the relative stereochemistry of palau'amine, 4-bromopalau'amine, styloguanidine, 3-bromostyloguanidine, and 2,3-dibromostyloguanidine should also be revised to 12R, 17S, 20S. Stylissadines A and B are the most potent natural product P2X7 antagonists to be isolated to date and provide a novel class of P2X7 receptor inhibitors. They are also the first examples of tetrameric pyrrole-imidazole alkaloids.
Asunto(s)
Antiinflamatorios/química , Productos Biológicos/química , Imidazoles/química , Antagonistas del Receptor Purinérgico P2 , Pirroles/química , Animales , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Poríferos/químicaRESUMEN
A series of 3-(4-hydroxyphenyl) propanoic acid derivatives, which inhibit Itk (interleukin-2 inducible T-cell kinase), a Th2-cell target, were isolated from the Australian rainforest tree Polyscias murrayi. The new compound 3-(4-hydroxyphenyl) propionyl choline and a 2:1 mixture of the new compounds 3,4-di-O-3-(4-hydroxyphenyl) propionyl-1,5-dihydroxycyclohexanecarboxylic acid and 3,5-di-O-3-(4-hydroxyphenyl) propionyl-1,4-dihydroxycyclohexanecarboxylic acid were isolated along with two known compounds 3-(4-hydroxyphenyl) propanoic acid and 3-(3,4-hydroxyphenyl) propanoic acid. Their structures were determined by 1D and 2D NMR spectroscopy. The assay results suggest that both the 3-(4-hydroxyphenyl) propanoate and carboxyl moieties contribute to Itk activity of the compounds.
Asunto(s)
Araliaceae/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Árboles/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Proteínas Tirosina Quinasas/metabolismo , LluviaRESUMEN
Three new marine natural products, dysinosins B-D (1-3), were isolated from the sponge Lamellodysidea chlorea and their structures determined by 1D and 2D NMR spectroscopy. These compounds are inhibitors of the blood coagulation cascade serine proteases factor VIIa and thrombin. These analogues, dysinosins B-D (1-3), allowed identification of two structural motifs within the structures that contribute to binding to the proteases, factor VIIa and thrombin.