RESUMEN
Mimicking the transition state of tryptophan (Trp) and O2 in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC50 of 82-91 nM, and exhibited selectivity between IDO1 and tryptophan 2,3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.
Asunto(s)
Benzoxazoles , Diseño de Fármacos , Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Lipopolisacáridos , Animales , Ratones , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células RAW 264.7 , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Benzoxazoles/farmacología , Benzoxazoles/química , Benzoxazoles/síntesis química , Estructura Molecular , Edema/tratamiento farmacológico , Edema/inducido químicamente , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis química , Relación Dosis-Respuesta a Droga , Inflamación/tratamiento farmacológico , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , MasculinoRESUMEN
Total syntheses of two γ-butenolide natural products, asperjinone (1) and asperimide C (2) in both racemic and chiral forms have been accomplished utilizing Basavaiah's one-pot Friedel-Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of 1 proposed by Williams et al. and the structure and absolute configuration of 2 reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of 1. Synthetic 1 exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 under LPS-induced renal inflammation condition and was superior to (S)-1, rac-2, 2, and a positive drug control, indomethacin. Moreover, compound 1 inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (1) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.
Asunto(s)
Antiinflamatorios , Animales , 4-Butirolactona/análogos & derivados , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Ciclooxigenasa 2/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Twenty-nine sesquiterpenoids, including pseudoguaiane-type (1-11), eudesmane-type (12-23), and carabrane-type (24-29), have been identified from the plant Carpesium abrotanoides. Of them, compounds 1-4, 12-15, and 24-27, namely carpabrotins A-L, are twelve previously undescribed ones. Compound 3 possessed a pseudoguaiane backbone with a rearrangement modification at C-11, C-12 and C-13, while compound 4 suffered a carbon bond break between the C-4 and C-5 to form a rare 4,5-seco-pseudoguaiane lactone. Compounds 1-3, 5, 13-16 and 25-27 exhibited anti-inflammatory activity by inhibiting NO production in LPS-induced RAW264.7 macrophages with IC50 values less than 40 µM, while compounds 1, 2, 5, 13, 14, 16, and 25-27 showed significant inhibitory activity comparable to that of dexamethasone. The anti-atopic dermatitis (AD) effects of compounds 5 and 16 were tested according to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in KM mice, and the results revealed that the major products 5 and 16 improved the histological features of AD-like skin lesions and mast cell infiltration in mice. This study suggested that sesquiterpenoids in C. abrotanoides should play a key role in its anti-inflammatory use.
Asunto(s)
Asteraceae , Óxido Nítrico , Sesquiterpenos , Animales , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Asteraceae/química , Células RAW 264.7 , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Macrófagos/efectos de los fármacos , MasculinoRESUMEN
As one of a traditional Chinese medicine with dual applications in both medicinal treatment and dietary consumption, the mature seeds of D. lablab were reported to be rich in saponins and have a good effect on inflammatory related diseases. However, the substance basis for its anti-inflammatory activity remains unclear. Thus, a comprehensive phytochemical investigation on triterpenoid saponins from D. lablab seeds was carried out, resulting in the isolation and identification of twenty-one new triterpenoid saponins including dolilabsaponins A1-A4, B, C, D1-D3, E-M, N1, N2 and O (1-21) along with thirteen known analogs (22-34). Notably, the known saponins, 31, 32, and 34 were obtained from Leguminosae family for the first time. The 1H and 13C NMR data of saponins 24 and 28 were firstly reported here. Additionally, lipopolysaccharide (LPS)-stimulated RAW264.7 cells model was utilized to assess inhibitory activities of compounds 1-34 on nitric oxide (NO) production. The results revealed that compounds 1-3, 9, 10, 13-15, 18, 22, 23 and 28-34 significantly suppressed the elevation of NO levels in LPS-induced RAW264.7 cells at the concentration of 30 µM, exhibiting a concentration-dependent manner at 3, 10, and 30 µM. The results suggested that compounds 1-3, 9, 10, 13-15, 18, 22, 23, and 28-34 possessed potential anti-inflammatory activity. Further western blot assay demonstrated that 1, 9, 10, 13, 14, and 18 suppressed inflammatory response via down-regulated the expression levels of inflammatory factors, tumor necrosis factor-alpha and interleukin-6.
Asunto(s)
Dolichos , Lipopolisacáridos , Óxido Nítrico , Saponinas , Semillas , Saponinas/farmacología , Saponinas/química , Saponinas/aislamiento & purificación , Ratones , Células RAW 264.7 , Animales , Semillas/química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Dolichos/química , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificaciónRESUMEN
Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.
Asunto(s)
Ácido Oleanólico , Ratones , Animales , Células RAW 264.7 , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análogos & derivados , Estructura Molecular , Relación Estructura-Actividad , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Phytochemical investigation of the 70% ethanol extract of Isodon henryi Kudô afforded fifteen ent-kaurane diterpenoids, including nine previously undescribed compounds, named isohenolides C-K (1-9). Compounds 1-6 featured an unusual 6,7;8,15-diseco-7,20-olide ent-kaurane diterpenoid scaffold, in which 1 also possessed an 11,15-lactone ring while 2-6 all contained a free α-methylene-γ-carboxylic acid. Compound 6 was also a rare 6,8-cyclo-7,20-olide ent-kauranoid. Their structures were elucidated primarily by HRESIMS, 1D and 2D NMR spectroscopy, electronic circular dichroism and X-ray diffraction (Cu Kα) methods. Additionally, most compounds were also screened for anti-inflammatory actions against lipopolysaccharide-induced RAW 264.7 cells, and compounds 9 and 13 exhibited stronger nitric oxide inhibition, with IC50 values of 15.99 ± 0.75 and 18.19 ± 0.42 µM, respectively.
Asunto(s)
Antiinflamatorios , Diterpenos de Tipo Kaurano , Isodon , Lipopolisacáridos , Óxido Nítrico , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/aislamiento & purificación , Ratones , Animales , Células RAW 264.7 , Isodon/química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Estructura Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Conformación Molecular , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificaciónRESUMEN
Fourteen undescribed diterpenoids, including eleven lathyrane diterpenoids wallathyanes A-K (1-11) and three ent-isopimarane diterpenoids wallisopiranes A-C (12-14), together with fourteen known analogues 15-28, were obtained from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallography. Bioactivity screening indicated that compound 2 exhibited an inhibitory effect on NO generation in LPS-stimulated RAW264.7 macrophage cells with an IC50 value of 4.76 ± 1.08 µM. The network pharmacology and molecular docking studies also revealed that compound 2 can bind with the potential targets GRB, AKT1, MAPK1, MAPK14, HSP90AA1, PIK3R1, PIK3CB, PRKACA, SRC, CASP3, RXRA, PTPNA11, ZAP70, and PRKC of inflammation.
Asunto(s)
Diterpenos , Euphorbia , Euphorbia/química , Diterpenos/química , Diterpenos/farmacología , Diterpenos/aislamiento & purificación , Ratones , Animales , Células RAW 264.7 , Estructura Molecular , Simulación del Acoplamiento Molecular , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Macrófagos/efectos de los fármacos , Macrófagos/metabolismoRESUMEN
Anemone vitifolia is a small herb found in Asia that is used to treat a range of diseases in Chinese traditional medicine. GNPS-based molecular networking of an Anemone vitifolia specimen revealed the presence of a network containing numerous ions indicating the presence of lignans, several of which suggested that there might be previously undescribed compounds in the extract. Fractionation of the organic extract yielded five undescribed lignans, the vitifolignans, together with one known. The structures were identified based on extensive spectroscopic data analysis (NMR, HR-ESI-MS, and UV), coupling constant calculation and comparison with reported data. Their absolute configurations were determined by comparison of experimental ECD spectra with calculated spectra. Compounds 4/5 showed weak inhibition of LPS-induced NO production in mouse mononuclear macrophages.
Asunto(s)
Anemone , Lignanos , Lipopolisacáridos , Óxido Nítrico , Lignanos/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Animales , Ratones , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Anemone/química , Estructura Molecular , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Furanos/química , Furanos/aislamiento & purificación , Furanos/farmacologíaRESUMEN
UPLC-Q-TOF-MS combined with mass defect filtering strategies were applied for the phytochemical investigation of Harrisonia perforata, leading to the isolation of thirteen undescribed limonoids named haperforatones A-M (1-13) and seventeen known compounds (14-30). Particularly, haperforatones D-E (4-5) have an unprecedented A, B, C, D-seco-6, 7-nor-C-24-limonoid skeleton, structurally stripped of the five-membered lactone ring B and formed a double bond at the C-5 and C-10 positions. Their 2D structures and relative configurations were identified using spectroscopic data. The absolute configurations of 1, 4, and 6 were established via X-ray diffraction crystallography. All 30 compounds were evaluated for anti-inflammatory potential in LPS-induced Raw 264.7 cell lines. Among those tested compounds, the most potent activity against LPS-induced NO generation was demonstrated by haperforatone F (6), with the IC50 value of inhibition NO production of 7.2 µM. Additionally, 6 could significantly inhibit IL-1ß and IL-6 release and markedly downregulate the protein expression level of iNOS in the LPS-stimulated RAW264.7 cells at 10 µM. The possible mechanism of NO inhibition of 6 was also investigated using molecular docking, which revealed the interaction of compound 6 with the iNOS protein.
Asunto(s)
Limoninas , Lipopolisacáridos , Óxido Nítrico , Ratones , Limoninas/farmacología , Limoninas/química , Limoninas/aislamiento & purificación , Animales , Células RAW 264.7 , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Relación Estructura-Actividad , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Relación Dosis-Respuesta a Droga , Meliaceae/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
One new canthinone glycoside (1), together with six known compounds (2-7) including three lignans (2-4), two coumarins (5-6) and one phenol (7) was isolated from the root barks of Ailanthus altissima. The structure of new compound 1 was established by the interpretation of UV, IR, MS and NMR data, while its absolute configuration was determined by acid hydrolysis and GIAO NMR calculations with DP4+ probability analysis. The inhibitory effects of all compounds on Nitric oxide (NO) production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 2 and 5 displayed NO production inhibitory activity with IC50 values of 30.1 and 15.3 µM, respectively.
Asunto(s)
Ailanthus , Glicósidos , Lipopolisacáridos , Óxido Nítrico , Corteza de la Planta , Raíces de Plantas , Ailanthus/química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Ratones , Estructura Molecular , Animales , Corteza de la Planta/química , Raíces de Plantas/química , Células RAW 264.7 , Glicósidos/farmacología , Glicósidos/química , Glicósidos/aislamiento & purificación , Lipopolisacáridos/farmacología , Lignanos/farmacología , Lignanos/química , Lignanos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Cumarinas/farmacología , Cumarinas/química , Cumarinas/aislamiento & purificación , Resonancia Magnética Nuclear BiomolecularRESUMEN
Sesquiterpene dimers are mainly found in the Asteraceae family. However, conflicting reports on the structures of these compounds can be found in the literature. Herein, we describe ten sesquiterpene dimers isolated from the flowers of Inula japonica, including configurational revisions of japonicone H (1-1), japonicone D (2-1), inulanolide A (4-1), japonicone X (5-1), and inulanolide F (5-2) to compounds 1, 2, 4, and 5, respectively. Five new related metabolites (3 and 6-9) are also described. Application of GIAO NMR/DP4+ analyses and ECD/OR calculations enabled us to revise the absolute configurations of an additional 13 sesquiterpene dimers isolated from plants of the genus Inula. Compounds 1, 2, 4, and 6 exhibited inhibition of nitric oxide production in lipopolysaccharide activated RAW264.7 macrophages with IC50 values of 4.07-10.00 µM.
Asunto(s)
Flores , Inula , Óxido Nítrico , Sesquiterpenos , Flores/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Inula/química , Ratones , Animales , Células RAW 264.7 , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , DimerizaciónRESUMEN
Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.
Asunto(s)
Antiinflamatorios , Asteraceae , Frutas , Óxido Nítrico , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Asteraceae/química , Frutas/química , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacologíaRESUMEN
Our ongoing exploration of Australian rainforest plants for the biodiscovery of anti-inflammatory agents led to the isolation and structural elucidation of eight new arylalkenyl α,ß-unsaturated-δ-lactones, triplinones A-H (1-8), from the leaves of the Australian rainforest plant Cryptocarya triplinervis B. Hyland (Lauraceae). The chemical structures of these compounds were established by NMR spectroscopic data analysis, while their relative and absolute configurations were established using a combination of Mosher ester analysis utilizing both Riguera's and Kishi's methods, ECD experiments, and X-ray crystallography analysis. Compounds 1-8 exhibited good inhibitory activities toward nitric oxide (NO) production in lipopolysaccharide (LPS) and interferon (IFN)-γ induced RAW 264.7 macrophages, in particular compounds 1-3 and 5, with IC50 values of 7.3 ± 0.5, 6.0 ± 0.3, 5.6 ± 0.3, and 5.4 ± 2.5 µM, respectively.
Asunto(s)
Antiinflamatorios , Cryptocarya , Lactonas , Óxido Nítrico , Hojas de la Planta , Bosque Lluvioso , Hojas de la Planta/química , Ratones , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Australia , Células RAW 264.7 , Estructura Molecular , Lactonas/farmacología , Lactonas/química , Lactonas/aislamiento & purificación , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Cryptocarya/química , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Cristalografía por Rayos XRESUMEN
Design, synthesis, and biological evaluation of two series of O4'-benzyl-hispidol derivatives and the analogous corresponding O3'-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4'-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3'-benzyl derivatives series. The most potential compound 2e of O4'-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3'-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.
Asunto(s)
Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Relación Estructura-Actividad , Animales , Ratones , Humanos , Estructura Molecular , Línea Celular , Relación Dosis-Respuesta a Droga , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Supervivencia Celular/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/químicaRESUMEN
Two previously undescribed coumarins (1-2) were isolated from the root of Notopterygium incisum. The structures of new findings were elucidated by analyses of spectral evidences in HRESIMS, NMR, as well as ICD. The absolute configurations were further confirmed by chemical calculations. 1-2 exhibits obviously anti-inflammatory activity by inhibiting the expression of inflammatory mediators (COX-2, iNOS), as well as reducing the release of NO and the accumulation of ROS in cells. Western blotting analysis revealed that 2 could inhibit the PI3K/AKT pathway by reducing the expression of p-PI3K and p-AKT.
Asunto(s)
Apiaceae , Cumarinas , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Apiaceae/química , Cumarinas/química , Cumarinas/farmacología , Cumarinas/aislamiento & purificación , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Raíces de Plantas/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Relación Estructura-Actividad , Nitrilos/químicaRESUMEN
A new monoterpene, (-)-10-hydroxydihydroactinidiolide (1), along with two known monoterpenes, loliolide (2) and (+)-isololiolide (3), three known megastigmanes, 3α-hydroxy-5ß,6ß-epoxy-ß-ionone (4), 3α-hydroxy-5α,6α-epoxy-ß-ionone (5), and (+)-dehydrovomifoliol (6), a eudesmane-type sesquiterpene, 4α-hydroxy-4ß-methyldihydrocostol (7), a monoterpene, 8-hydroxycarvotanacetone (8), two flavonoids, chrysoeriol (9) and apigenin (10), and a phenylpropanoid, 3-(4-hydroxyphenyl)-1-propanol (11), were isolated from the whole plant of Achillea millefolium. The structure of compound 1 was identified according to spectroscopic data of HRMS and NMR, and its absolute configuration was assigned by 13Câ NMR calculations with DP4+ probability analyses and ECD calculations. The absolute configuration of compound 6 was determined by ECD calculations. Compounds 3, 6, 9 and 10 could dose-dependently inhibit the NO release in LPS-induced RAW264.7 cells.
Asunto(s)
Achillea , Antiinflamatorios , Achillea/química , Ratones , Animales , Células RAW 264.7 , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Meliasanines A-L, twelve previously unreported tirucallane-type triterpenoids, together with fifteen known ones, have been isolated from the stem bark of Melia toosendan. Their structures and absolute configurations were determined based on HRESIMS, and NMR, combined with calculated ECD and single-crystal X-ray diffraction analyses. Subsequently, all compounds except 10 were evaluated for their inhibitory effect on the production of nitric oxide induced by lipopolysaccharide in RAW264.7 macrophage cells. The results indicated that seven compounds (1, 13, 14, 16, 20, 22, and 23) exhibited significant NO inhibitory effects, with IC50 values ranging from 1.35 to 5.93 µM, which were more effective than the positive control indomethacin (IC50 = 13.18 µM). Moreover, the corresponding results of Western blot analysis revealed that meliasanine A (1) can significantly suppress the protein expression of inducible nitric oxide synthase and cyclooxygenase 2 in a concentration-dependent manner. The mechanism study suggested that meliasanine A exerts an anti-inflammatory effect via the nuclear factor-κB signaling pathway by suppressing phosphorylation of P65 and IκBα.
Asunto(s)
Antiinflamatorios , Lipopolisacáridos , Melia , FN-kappa B , Óxido Nítrico , Transducción de Señal , Triterpenos , Ratones , Animales , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Estructura Molecular , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Melia/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Corteza de la Planta/química , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Relación Estructura-ActividadRESUMEN
Citristerones A-E (1-5), five new 23,24-diols containing ergosterols, along with three known analogues, were isolated from the endophytic fungus Penicillium citrinum TJ507 obtained from Hypericum wilsonii N. Robson. Their structures and absolute configurations were determined by NMR, HRESIMS, Snatzke's method, X-ray diffraction analyses and ECD calculation. Subsequently, the anti-neuroinflammatory effects of these isolates were screened using lipopolysaccharide (LPS)-induced BV-2 microglial cells, and citristerone B (2) showed outstanding anti-neuroinflammatory activity, with IC50 value of 0.60 ± 0.04 µM. Moreover, immunofluorescence and western blot analysis suggested that citristerone B not only reduced the release of nitric oxide (NO) and proinflammatory cytokines in LPS-induced BV-2 microglial cells, but also significantly inhibited the expression of TNF-α, iNOS and NF-κB, along with the production of cellular ROS.
Asunto(s)
Relación Dosis-Respuesta a Droga , Lipopolisacáridos , Penicillium , Penicillium/química , Ratones , Animales , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Estructura Molecular , Relación Estructura-Actividad , Microglía/efectos de los fármacos , Microglía/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Descubrimiento de Drogas , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificaciónRESUMEN
Axially chiral compounds are well known in medicinal chemistry of natural products, but their absolute configurations and bioactivities are rarely reported and studied. In this study, eleven undescribed axially chiral dihydrophenanthrene dimers, as well as twenty-five known dihydrophenanthrenes, were isolated from the entire plant of Pholidota yunnanensis. Their structures were elucidated by comprehensive spectroscopic analysis. A method for determining the absolute configurations of enantiomers was developed based on the rotational barriers and calculated ECD spectra. Additionally, the activities of all isolated compounds were assessed in LPS-induced BV-2 microglial cells. Most dihydrophenanthrenes exhibited significant NO inhibitory activities, and compound 7 showed the most potent inhibitory effect with an IC50 value of 1.5 µM, compared to the positive control minocycline. The immunofluorescence and western blot results revealed that compound 7 suppressed the expression of Iba-1, iNOS and COX-2 in LPS-stimulated BV-2 microglial cells.
Asunto(s)
Lipopolisacáridos , Microglía , Fenantrenos , Fenantrenos/farmacología , Fenantrenos/química , Fenantrenos/aislamiento & purificación , Animales , Ratones , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Microglía/efectos de los fármacos , Microglía/metabolismo , Relación Estructura-Actividad , Dimerización , Relación Dosis-Respuesta a Droga , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Orchidaceae/química , Línea Celular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , EstereoisomerismoRESUMEN
Eleven alkaloids including four previously undescribed oxoisoaporphine alkaloids, menisoxoisoaporphines A-D (1-4), four known analogues (5-8), and three aporphine alkaloids (9-11), were isolated and identified from the rhizomes of Menispermum dauricum. Their structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction analyses. Among them, compounds 1 and 4 were the first samples of oxoisoaporphine with C-6 isopentylamino moiety, and 2 was a rare C-4 methylation product of oxoisoaporphine alkaloid. The in vitro anti-inflammatory activity of compounds 1-11 was performed by evaluating the inhibition of NO level in LPS-induced RAW264.7 macrophages. Among them, compound 4 exhibited the most potent NO inhibition activity with an IC50 value of 1.95 ± 0.33 µM. The key structure-activity relationships of those oxoisoaporphine alkaloids for anti-inflammatory effects have been summarized.