RESUMEN
Two undescribed prenylated quinolinone alkaloids, aspoquinolones E and F, and three undescribed prenylated isoindolinone alkaloids aspernidines F-H, were isolated from the fungus Aspergillus nidulans. Their structures and configurations were elucidated based on spectroscopic analyses and ECD spectra. Aspoquinolones E and F possess a C10 moiety with an unusual 2,2,4-trimethyl-3oxa-bicyclo[3.1.0]hexane unit, and aspernidines F-H own a C15 side chain. These compounds were evaluated for cytotoxic activities against five human cancer cell lines, compounds 1 and 5 exhibited strong inhibitory activities against A-549 and SW-480â¯cells with IC50 values of 3.50 and 4.77⯵M, respectively.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Aspergillus nidulans/química , Ftalimidas/farmacología , Quinolonas/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Ftalimidas/química , Ftalimidas/aislamiento & purificación , Prenilación , Quinolonas/química , Quinolonas/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
The absolute configurations of the diastereomers of novel amino acid ester derivatives of 2,3-substituted isoindolinones, which are known as apoptosis activators due to their ability to inhibit the MDM2-p53 PPI, were assigned using NMR and computational methods. Procedures for diastereomer separation and determining the absolute configuration were developed to perform the study. The high significance of N-benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S- and R-isoindolinone L-valinates differs by less than 20%. It can be explained by the presence of a flexible linker between the isoindolinone core and amino acid fragment, which provides the optimal arrangement of the molecule in the hydrophobic cavity of MDM2 for both isomers.
Asunto(s)
Aminoácidos/química , Ftalimidas/química , Ftalimidas/farmacología , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Ftalimidas/aislamiento & purificación , Ftalimidas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Protones , Estereoisomerismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A pair of 3-arylisoindolinone enantiomers: (+)-asperglactam A (1), (-)-asperglactam A (1) and a pair of nor-bisabolane enantiomers: (+)-1-hydroxyboivinianic acid (2), (-)-1-hydroxyboivinianic acid (2), along with seven known compounds (3-8) were obtained from the mangrove endophytic fungus Aspergillus versicolor SYSU-SKS025. Their structures were determined on the basis of HRESIMS and NMR spectroscopic data, and X-ray diffraction. (+)-Asperglactam A (1) and (-)-asperglactam A (1) are the first optically pure examples in the 3-arylisoindolinone family, which are rarely found in natural sources. All isolated compounds were evaluated for α-glucosidase inhibitory activity. The enantiomers of 1-3 showed moderate inhibitory activity against α-glucosidase with IC50 values ranging from 50 to 190µM. Compound 7 exhibited significant inhibitory activity against α-glucosidase with IC50 value of 7.5µM. In addition, compound 7 was found to inhibit nitric oxide production in RAW 264.7 macrophages with IC50 value of 12.5µM.
Asunto(s)
Aspergillus/química , Euphorbiaceae/microbiología , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Ftalimidas/aislamiento & purificación , Sesquiterpenos/aislamiento & purificación , Animales , Endófitos/química , Inhibidores de Glicósido Hidrolasas/química , Ratones , Estructura Molecular , Ftalimidas/química , Células RAW 264.7 , Sesquiterpenos/química , Estereoisomerismo , alfa-GlucosidasasRESUMEN
Three new phthalide derivatives, emefuranones A1, A2 and B (1-3); six new phthalane derivatives, emefuran A, B1, B2, C1, C2 and D (4-9); three new farnesylated phthalide derivatives, farnesylemefuranones A-C (10-12); xylarinol C (13); and emericelloxide (14), along with four known compounds (dustanin, sorbicillin, aspergillodiol and xylarinol A), were isolated from the culture extracts of Emericella sp. IFM57991. Structures of 1-14 were elucidated on the basis of spectroscopic analysis and chemical evidence. Compounds 4-7 and 13 showed moderate antibacterial activities against Bacillus subtilis.
Asunto(s)
Antiinfecciosos/farmacología , Bacillus subtilis/efectos de los fármacos , Benzofuranos/farmacología , Medios de Cultivo/química , Emericella/metabolismo , Ftalimidas/farmacología , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Benzofuranos/química , Benzofuranos/aislamiento & purificación , Pruebas Antimicrobianas de Difusión por Disco , Emericella/crecimiento & desarrollo , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Ftalimidas/química , Ftalimidas/aislamiento & purificaciónRESUMEN
The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues.
Asunto(s)
Abietanos/química , Antimaláricos/química , Ftalimidas/química , Extractos Vegetales/química , Abietanos/aislamiento & purificación , Abietanos/farmacología , Animales , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Células CHO , Cricetinae , Cricetulus , Células Hep G2 , Humanos , Ftalimidas/aislamiento & purificación , Ftalimidas/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/fisiologíaRESUMEN
The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H)-dione, isolated from the mushroom-forming fungus Flammulina velutipes, in both racemic and enantiomeric pure forms, is reported. The (-)-enantiomer of the natural product has been synthesized from the D-(-)-pantolactone chiral pool. The synthesis features a one-pot, three-step reaction sequence comprising an enyne RCM/Diels-Alder/aromatization to construct the desired indane skeleton present in the natural product. Our synthesis further confirms the assigned structure and absolute configuration of the natural product.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/aislamiento & purificación , Antineoplásicos/síntesis química , Antineoplásicos/aislamiento & purificación , Flammulina/química , Ftalimidas/síntesis química , Ftalimidas/aislamiento & purificación , Alcaloides/química , Alcaloides/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ftalimidas/química , Ftalimidas/farmacología , EstereoisomerismoRESUMEN
A marine-derived fungus of the genus Stachylidium was isolated from the sponge Callyspongia cf. C. flammea. Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A(1) (1a), A(2) (1b), B (2), and C (3). The absolute configurations of the enantiomeric compounds 1a and 1b were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A(1) (1a) and A(2) (1b), inhibited human leukocyte elastase (HLE) with an IC(50) value of 0.86 µM.
Asunto(s)
Ascomicetos/química , Elastasa de Leucocito/antagonistas & inhibidores , Ftalimidas/aislamiento & purificación , Poríferos/microbiología , Animales , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Ftalimidas/química , Ftalimidas/farmacologíaRESUMEN
A method for the determination of flumioxazin residue in foods by gas chromatography-mass spectrometry (GC-MS) has been developed. The food sample was extracted with acetonitrile or ethyl acetate, concentrated in a rotary evaporator, then dissolved in acetonitrile-methyl benzene (3 : 1, v/v) and purified with an NH2-solid phase extraction (SPE) column. The final extract was analyzed by gas chromatography-mass spectrometry with selected ion monitoring mode (GC-MS-SIM). External standard method was used for the quantification. The mean recoveries of flumioxazin spiked in foods were 79.4% - 101%, and the relative standard deviations were 0.242% -7.15% (n = 10). The detection limit for each was 0.01 mg/kg. This method has high sensitivity, veracity and is suitable for the determination of pesticide residues in foods.
Asunto(s)
Benzoxazinas/análisis , Análisis de los Alimentos/métodos , Contaminación de Alimentos/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Residuos de Plaguicidas/análisis , Ftalimidas/análisis , Animales , Benzoxazinas/aislamiento & purificación , Ácidos Grasos/química , Ácidos Grasos/aislamiento & purificación , Límite de Detección , Modelos Lineales , Residuos de Plaguicidas/aislamiento & purificación , Ftalimidas/aislamiento & purificación , Reproducibilidad de los Resultados , Solventes/química , Factores de TiempoRESUMEN
[reaction: see text] A synthesis of the glutarimide-derived metabolite of thalidomide, 5'-hydroxythalidomide (2), is described. The synthesis employed the lactone derivative of N-benzyloxycarbonyl (CBZ)-protected 4-hydroxyglutamic acid 12, which is prepared by a de novo route from diethyl acetamidomalonate. The reaction of 12 with 4-methoxybenzylamine gave the corresponding isoglutamine, which then provided the key CBZ-protected N-PMB-glutarimide 14 after dehydration. Deprotection of both the CBZ and PMB groups followed by phthalimidation and deacetylation of the 3-amino-5-acetoxyglutarimide 16 afforded 2.
Asunto(s)
Ftalimidas/síntesis química , Ftalimidas/aislamiento & purificación , Piperidonas/síntesis química , Piperidonas/aislamiento & purificación , Talidomida/química , Humanos , Estructura Molecular , Ftalimidas/química , Piperidonas/química , Estereoisomerismo , Talidomida/metabolismoRESUMEN
Radiolabelled Sch 13835, an inhibitor of platelet derived growth factor, was prepared by catalytic hydrogenolysis of a benzyl bromide precursor with tritium gas. Regular and deactivated reversed-phase HPLC stationary phases gave poor peak shapes and little resolution of Sch 13835 and the benzyl bromide precursor. Fluorodecyl and fluoroether stationary phases in the analytical reversed-phase mode gave baseline separation using organic-aqueous (no buffers) mobile phases. Elution orders were reversed on either phase by a change in the organic component from methanol to acetonitrile. The product is unstable in aqueous (or other protic) solvents, forming a ring-opened acid. Conditions were developed to successfully purify the compound by reversed-phase HPLC with minimal decomposition. A second analytical HPLC assay was developed using normal-phase solvents on a fluoroether stationary phase.
Asunto(s)
Clorobencenos/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Flúor/química , Ftalimidas/aislamiento & purificación , Sulfonamidas/aislamiento & purificación , Clorobencenos/análisis , Clorobencenos/química , Ftalimidas/análisis , Ftalimidas/química , Espectrofotometría Ultravioleta , Sulfonamidas/análisis , Sulfonamidas/química , TritioRESUMEN
The chromatographic behaviour of phthalimide derivatives during thin-layer chromatography on silica gel is explained by the repercussions of mesomeric and inductive effects on the specific combined action of the oxygen of the carbonyl groups and of protonized hydrogen atoms of the active centres on the surface of the adsorbent. It is shown that within the groups of solvents the products of the eluting power of the solvent by the activity of the adsorbent is proportional to the amount of the Rf value.