RESUMO
A methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) showed anti-proliferative activity against human prostate carcinoma LNCaP cells (IC50 = 2.0 µg/mL). Two new coumarin-related polysubstituted benzofurans, mammeasins P (1) and Q (2), and a known polysubstituted coumarin mammea B/AC cyclo F (39) were isolated from the extract along with 44 previously reported polysubstituted coumarin constituents (3-38 and 40-47). The structures of two new compounds (1 and 2) were determined based on their spectroscopic properties derived from the physicochemical evidence including NMR and MS analyses and taking the plausible generative pathway into account. Among the coumarin constituents, mammeasins A (3, IC50 = 1.2 µM) and B (4, 0.63 µM), sugangin B (18, 1.5 µM), kayeassamins E (24, 3.0 µM) and G (26, 3.5 µM), and mammeas E/BA (40, 0.88 µM), E/BB (41, 0.52 µM), and E/BC (42, 0.12 µM) showed relatively potent anti-proliferative activity.
RESUMO
With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K (1), L (2), M (3), N (4), and O (5), were isolated from the methanolic extract of Mammea siamensis (Miq.) T. Anders. flowers (fam. Calophyllaceae), originating in Thailand. The stereostructures of 1-5 were elucidated based on their spectroscopic properties. Among the new compounds, 1 (IC50 = 7.6 µM) and 5 (9.1 µM) possessed relatively strong inhibitory activity against aromatase, which is a target of drugs already used in clinical practice for the treatment and prevention of estrogen-dependent breast cancer. The analysis through Lineweaver-Burk plots showed that they competitively inhibit aromatase (1, Ki = 3.4 µM and 5, 2.3 µM). Additionally, the most potent coumarin constituent, mammea B/AB cyclo D (31, Ki = 0.84 µM), had a competitive inhibitory activity equivalent to that of aminoglutethimide (0.84 µM), an aromatase inhibitor used in therapeutics.
Assuntos
Mammea , Plantas Medicinais , Aminoglutetimida , Aromatase , Inibidores da Aromatase/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Estrogênios/farmacologia , Mammea/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , TailândiaRESUMO
Geranylated coumarins named mammeasins G-J (1-4) were isolated from the methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) originating in Thailand. Their structures were established based on detailed spectroscopic analyses. The isolates, including previously reported coumarin constituents (5-28), exhibited anti-proliferative activities against human carcinoma cell lines HSC-2, HSC-4, MKN-45, and MCF-7. Mammeasin A (7, IC50 = 13.6 µM) and surangin B (15, 15.2 µM), both consisting of the geranyl group, were found to show relatively strong activities against HSC-4 cells and their mechanisms of action were found to involve apoptotic cell death.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/farmacologia , Neoplasias Gastrointestinais/patologia , Mammea/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Linhagem Celular Tumoral , Cumarínicos/isolamento & purificação , Flores/química , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , TailândiaRESUMO
Geranylated coumarin constituents, kayeassamin I (1) and mammeasins E (2) and F (3) were newly isolated from the methanol extract of the flowers of Mammea siamensis (Calophyllaceae) originating in Thailand, along with five known isolates, such as mammea E/BC (23), deacetylmammea E/AA cyclo D (31), deacetylmammea E/BB cyclo D (32), mammea A/AA cyclo F (34), and mammea A/AC cyclo F (35). These compounds (1-3) were obtained as an inseparable mixture (ca. 1:1 ratio) of the 3â³R and 3â³S forms, respectively. Among the isolated coumarins from the extract, mammeasins E (2, 22.6 µM), A (4, 19.0 µM), and B (5, 24.0 µM), kayeassamins E (9, 33.8 µM), F (10, 15.9 µM), and G (11, 17.7 µM), surangin C (13, 5.9 µM), and mammeas A/AA (17, 19.5 µM), E/BB (22, 16.8 µM), and A/AA cyclo F (34, 23.6 µM), were found to inhibit testosterone 5α-reductase.
RESUMO
A hitherto unreported member of γ-alkylidenebutenolides in Melodorum fruticosum (Annonaceae), (4 E)-6-benzoyloxy-7-hydroxy-2,4-heptadiene-4-olide, named as isofruticosinol (4) was isolated from the methanol extract of flowers, along with the known related butenolides, namely, the (4 Z)-isomer (3) of 4, melodrinol (1), and its (4 E)-isomer (2). To unambiguously determine the absolute configuration at the C-6 position in these butenolides, the first total syntheses of both enantiomers of 2-4 were achieved over 6-7 steps from commercially available D- or L-ribose (D- and L-5). Using the same protocol, both enantiomers of 1 were also synthesized. Based on chiral HPLC analysis of all synthetic compounds ( S- and R-1-4), all naturally occurring butenolides were assigned as partial racemic mixtures with respect to the chiral center at C-6 (enantiomeric ratio, 6 S/6 R = â¼83/17). Furthermore, the melanogenesis inhibitory activities of S- and R-1-4 were evaluated, with all shown to be potent inhibitors with IC50 values in the range 0.29-2.9 µM, regardless of differences in the stereochemistry at C-6. In particular, S-4 (IC50 = 0.29 µM) and R-4 (0.39 µM) showed potent inhibitory activities compared with that of reference standard arbutin (174 µM).
Assuntos
4-Butirolactona/análogos & derivados , Annonaceae/química , Melaninas/biossíntese , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Animais , Linhagem Celular Tumoral , Técnicas de Química Sintética , Camundongos , Plantas Medicinais/químicaRESUMO
Two new aromatic glycosides, elengiosides A (1) and B (2), were isolated from the methanolic extract of the flowers of Mimusops elengi (Sapotaceae) together with 26 known compounds. Their stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Among the isolates, a phenylethanoid glycoside, undatuside C (14), was found to exhibit hyaluronidase inhibitory activity.
Assuntos
Flores/química , Glicosídeos/química , Mimusops/química , Extratos Vegetais/químicaRESUMO
In our continuing study of biologically active natural products from the fruit of Alpinia galanga (Zingiberaceae), we newly isolated three new labdane-type diterpenes, termed galangalditerpenes A-C (1-3), along with four known sesquiterpenes (4-7) and two diterpenes (8 and 9). The stereostructures of 1-3 were elucidated on the basis of their spectroscopic properties. The melanogenesis inhibitory activities in theophylline-stimulated murine B16 melanoma 4A5 cells of these isolates, including the new diterpenes (1-3, IC50 = 4.4, 8.6, and 4.6 µM, respectively), were found to be more than 6-87-fold higher than that of arbutin (174 µM), a commercially available positive control.
Assuntos
Alpinia/química , Diterpenos/química , Frutas/química , Melaninas/metabolismo , Animais , Arbutina/química , Arbutina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Melanoma Experimental , Camundongos , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
A simultaneous quantitative analytical method for 13 stilbenoids including (-)-hopeaphenol (1), (+)-isohopeaphenol (2), hemsleyanol D (3), (-)-ampelopsin H (4), vaticanols A (5), E (6), and G (7), (+)-α-viniferin (8), pauciflorol A (9), hopeafuran (10), (-)-balanocarpol (11), (-)-ampelopsin A (12), and trans-resveratrol 10-C-ß-d-glucopyranoside (13), and two dihydroisocoumarins, phayomphenols A1 (14) and A2 (15) in the extract of Shorea roxburghii (dipterocarpaceae) was developed. According to the established protocol, distributions of these 15 polyphenols (1-15) in the bark and wood parts of S. roxburghii and a related plant Cotylelobium melanoxylon were evaluated. In addition, the principal polyphenols (1, 2, 8, 13-15) exhibited hepatoprotective effects against d-galactosamine (d-galN)/lipopolysaccharide (LPS)-induced liver injury in mice at a dose of 100 or 200 mg/kg, p.o. To characterize the mechanisms of action, the isolates were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes; (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages; and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of these polyphenols (1, 2, and 8) were suggested to be dependent on the inhibition of LPS-induced macrophage activation and reduction of sensitivity of hepatocytes to TNF-α. However, none of the isolates reduced the cytotoxicity caused by d-GalN.
Assuntos
Dipterocarpaceae/química , Hepatócitos/efeitos dos fármacos , Isocumarinas/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Galactosamina/efeitos adversos , Hepatócitos/metabolismo , Humanos , Isocumarinas/química , Lipopolissacarídeos/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Polifenóis/química , Polifenóis/farmacologia , Substâncias Protetoras/química , Estilbenos/química , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50=7.3µg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC50=2.5µM), 1'S-1'-acetoxychavicol acetate (2, 5.0µM), and 1'S-1'-acetoxyeugenol acetate (3, 5.6µM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1'-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9'-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1' (IC50=1.9µM) and 2' (4.5µM)] and racemic mixtures [(±)-1 (2.2µM) and (±)-2 (4.4µM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1-3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.
Assuntos
Alpinia/química , Lignanas/farmacologia , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Frutas/química , Expressão Gênica , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Lignanas/química , Lignanas/isolamento & purificação , Melanócitos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , RNA Mensageiro/metabolismo , Estereoisomerismo , Teofilina/farmacologiaRESUMO
A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit enzymatic activity against aromatase (IC50=16.5 µg/mL). From the extract, two new geranylated coumarins, mammeasins C (1) and D (2), were isolated together with seven coumarins: 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(2-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (9), 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(3-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (10), mammeas A/AA (14), A/AB (15), A/AA cyclo D (18), E/BA (23), and E/BC cyclo D (25). The structures of 1 and 2 were elucidated on the basis of spectroscopic evidence. Among the isolates including 17 previously reported coumarins, 1 (IC50=2.7 µM), 2 (3.6 µM), and mammea B/AB cyclo D (21, 3.1 µM) showed relatively strong inhibitory activities comparable to the activity of the synthetic nonsteroidal aromatase inhibitor aminoglutethimide (2.0 µM).
Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Cumarínicos/farmacologia , Flores/química , Mammea/química , Inibidores da Aromatase/química , Inibidores da Aromatase/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
A methanol extract from the rhizomes of Kaempferia parviflora Wall. ex Baker (Zingiberaceae) has shown inhibitory effects against melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50 = 9.6 µg/mL). Among 25 flavonoids and three acetophenones isolated previously (1-28), several constituents including 5-hydroxy-7,3',4'-trimethoxyflavone (6, IC50 = 8.8 µM), 5,7,3',4'-tetramethoxyflavone (7, 8.6 µM), 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (12, 2.9 µM), and 5-hydroxy-3,7,3',4'-tetramethoxyflavone (13, 3.5 µM) showed inhibitory effects without notable cytotoxicity at the effective concentrations. Compounds 6, 7, 12, and 13 inhibited the expression of tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA, which could be the mechanism of their melanogenesis inhibitory activity. In addition, a quantitative analytical method for 12 methoxyflavones (1, 2, 4-11, 13, and 14) in the extract was developed using HPLC. The optimal condition for separation and detection of these constituents were achieved on an ODS column (3 µm particle size, 2.1 mm i.d. × 100 mm) with MeOH-0.1 % aqueous acetic acid solvent systems as the mobile phase, and the detection and quantitation limits of the method were estimated to be 0.08-0.66 ng and 0.22-2.00ng, respectively. The relative standard deviation values of intra- and interday precision were lower than 0.95 and 1.08 %, respectively, overall mean recoveries of all flavonoids were 97.9-102.9 %, and the correlation coefficients of all the calibration curves showed good linearity within the test ranges. For validation of the protocol, extracts of three kinds of the plant's rhizomes collected from different regions in Thailand (Leoi, Phetchabun, and Chiang Mai provinces) were evaluated. The results indicated that the assay was reproducible, precise, and could be readily utilized for the quality evaluation of the plant materials.
Assuntos
Flavonas/farmacologia , Melaninas/biossíntese , Zingiberaceae/química , Animais , Cromatografia Líquida de Alta Pressão , Flavonas/análise , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Melanoma Experimental , Camundongos , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , RNA Mensageiro/metabolismo , Rizoma/química , Tailândia , TeofilinaRESUMO
A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells. From the extract, two new geranylated coumarins, mammeasins A (1) and B (2), were isolated together with 17 known compounds including 15 coumarins. The structures of 1 and 2 were determined on the basis of their spectroscopic properties as well as of their chemical evidence. Among the isolates, 1 (IC(50) = 1.8 µM), 2 (6.4 µM), surangins B (3, 5.0 µM), C (4, 6.8 µM), and D (5, 6.2 µM), kayeassamins E (7, 6.1 µM), F (8, 6.0 µM), and G (9, 0.8 µM), mammea A/AD (11, 1.3 µM), and mammea E/BB (16, 7.9 µM) showed NO production inhibitory activity. Compounds 1, 9, and 11 were found to inhibit induction of inducible nitric oxide synthase (iNOS). With regard to mechanism of action of these active constituents (1, 9, and 11), suppression of STAT1 activation is suggested to be mainly involved in their suppression of iNOS induction.
Assuntos
Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Mammea/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Animais , Células Cultivadas , Cumarínicos/química , Cumarínicos/isolamento & purificação , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flores/química , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A methanol extract of the bark of Shorea roxburghii (Dipterocarpaceae) was found to inhibit plasma glucose elevation in sucrose-loaded mice. From the extract, three new 3-ethyl-4-phenyl-3,4-dihydroisocoumarins, 1'S-dihydrophayomphenol A(2) (1) and phayomphenols B(1) (2) and B(2) (3), were isolated together with 24 known compounds including 20 stilbenoids and oligostilbenoids. The structures of 1-3 were determined on the basis of their spectroscopic properties as well as of chemical evidences. Among the isolates, (-)-hopeaphenol (6), hemsleyanol D (8), (+)-α-viniferin (15), and (-)-balanocarpol (18) showed inhibitory activity against plasma glucose elevation in sucrose-loaded rats at doses of 100-200mg/kg, p.o. To clarify the mode of action of the antihyperglycemic property, effects of these oligostilbenoids on gastric emptying in mice, those on glucose uptake in isolated intestinal tissues as well as inhibitory activities against rat intestinal α-glucosidase and rat lens aldose reductase were examined.
Assuntos
Dipterocarpaceae/química , Hipoglicemiantes/química , Isocumarinas/química , Estilbenos/química , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/metabolismo , Animais , Metabolismo dos Carboidratos/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Isocumarinas/isolamento & purificação , Isocumarinas/farmacologia , Espectroscopia de Ressonância Magnética , Metanol/química , Camundongos , Conformação Molecular , Casca de Planta/química , Ratos , Estilbenos/isolamento & purificação , Estilbenos/farmacologia , alfa-Glucosidases/metabolismoRESUMO
Two new phenolic glycosides, kaempferiaosides A and B were isolated from the rhizomes of Kaempferia parviflora (Zingiberaceae) together with 24 known compounds. Their structures including absolute stereochemistry were elucidated on the basis of chemical and spectroscopic evidence. Among the isolates, 5,3'-dihydroxy-3,7,4'-trimethoxyflavone showed higher activity than silybin, a commercial hepatoprotective agent.
Assuntos
Glicosídeos/química , Hepatócitos/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Zingiberaceae/química , Animais , Células Cultivadas , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Fenóis/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Rizoma/químicaRESUMO
The methanol extract from the bark of Shorea roxburghii (Dipterocarpaceae, "Phayom" in Thai) was found to suppress plasma triglyceride elevation in olive oil-treated mice, and also to inhibit pancreatic lipase activity (IC(50) = 31.6 µg/ml). From the extract, two new 3-acetyl-4-phenyl-3,4-dihydroisocoumarins, phayomphenols A(1) (1) and A(2) (2) were isolated, together with 22 known compounds. The structures of 1 and 2 were elucidated on the basis of chemical and spectroscopic evidence, including X-ray crystallographic analysis. Among the isolates, several oligostilbenoids, including (-)-hopeaphenol (3) and (+)-isohopeaphenol (4), showed inhibitory effects on plasma triglyceride elevation at a dose of 200 mg/kg p.o. and pancreatic lipase inhibitory activity (IC(50) = 32.9 and 26.5 µM, respectively).
Assuntos
Dipterocarpaceae/química , Casca de Planta/química , Extratos Vegetais/química , Animais , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Lipase/metabolismo , Masculino , Camundongos , Azeite de Oliva , Extratos Vegetais/uso terapêutico , Óleos de Plantas/uso terapêuticoRESUMO
Two new flav-3-en-3-ol glycosides, kaempferiaosides C (3) and D(4), and two new acetophenone glycosides, kaempferiaosides E (5) and F (6), were isolated from the Thai natural medicine Krachai Dum, the rhizomes of Kaempferia parviflora Wall. ex Baker. Their structures were established mainly on the basis of 1D and 2D NMR spectral data.