Selective inhibition of aromatase by a dihydroisocoumarin from Xyris pterygoblephara

Aromatase is a well-established target for the chemoprevention of breast cancer. The dihydroisocoumarin (3 R,4 R)-(-)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1 H-isochromen-4-yl acetate (1) (IC 50 = 1.6 +/- 0.1 microM), isolated from aerial parts of Xyris pterygoblephara, showed aromatase inhibitory activity. The specificity of 1 was evaluated by inhibition assays with cytochrome P450 enzymes. CYP1A1 was inhibited modestly (IC 50 = 38.0 +/- 2.0 microM), while CYP2C8 and CYP3A4 enzymes were not affected. Dihydroisocoumarin 1 showed weak antiproliferative activity against MCF-7 (IC 50 = 66.9 +/- 2.3 microM) and LNCaP (IC 50 = 57.5 +/- 2.0 microM) cells and was inactive against LU-1 and HepG2 cells in culture. These results demonstrate the potential of dihydroisocoumarin 1 to serve as a selective aromatase inhibitor.     

Lignan derivatives and a norditerpene from the seeds of Vitex negundo

A new phenyldihydronaphthalene-type lignan, vitedoin A (1), a new phenylnaphthalene-type lignan alkaloid, vitedoamine A (2), and a new trinorlabdane-type diterpene, vitedoin B (3), were isolated from the seeds of Vitex negundo along with five known lignan derivatives (4-8). Their chemical structures were determined mainly on the basis of NMR and MS data. Compounds 1, 2, and 4-7 showed stronger antioxidative activity than alpha-tocopherol using the ferric thiocyanate method. Compounds 1, 2, and 4-7 showed higher radical-scavenging effect on the stable free radical, 1,1-diphenyl-2-picrylhydrazyl, than L-cysteine.     

油丹化学成分的研究

从油丹Ａｌｓｅｏｄａｐｈｎｅ ｈａｉｎａｎｅｎｓｉｓ Ｍｅｒｒ,树皮中分离得到４个化合物,根据ＨＲ－ＳＩＭＳ、＾１ＨＮＭＲ、＾１３ＣＮＭＲ及二维核磁共振技术鉴定其结构分别为：一个木脂素ｅｕｓｉｄｅｒｉｎ Ａ「７Ｒ,８Ｒ）－３,４,５,３’－四甲氧基－△＾８’,９’－８－Ｏ－４‘,７－Ｏ－５’木脂素」（Ⅰ）;两个苄基异喹啉类生物碱（６,７－二甲氧基异喹啉基）－（４’－甲氧基苯基）甲酮（Ⅱ）、（６,７     

Lignan glycosides from Neoalsomitra integrifoliola

Five new lignan glycosides, (8R*,7' S*,8' R*)-5,5'-dimethoxy-7-oxolariciresinol 9'-O-beta-D-xylopyranoside (1), (7S,8R)-dihydrodehydrodiconiferyl alcohol 9-O-beta-D-apiofuranosyl-(1-->6)-O-beta-D-glucopyranoside (2), (7S*,8R*,7' S*,8' R*)-4,4'-dimethoxyhuazhongilexin 9-O-beta-D-xylopyranoside (4), (7S*,8R*,7' S*,8' R*)-4,4'-dimethoxyhuazhongilexin 9-O-alpha-L-arabinopyranoside (5), and (7S*,8R*,7' S*,8' R*)-huazhongilexin 9-O-(2-feruloyl)-beta-D-xylopyranoside (6), together with four known compounds, (7R,8S)-dihydrodehydrodiconiferyl alcohol 9-O-beta-D-glucopyranoside (3), the 9-O-beta-D-xylopyranoside of icariol A(2) (7), huazhongilexin (8), and nudiposide (9), were isolated from the leaves of Neoalsomitra integrifoliola. Their structures were determined by spectroscopic analysis and chemical methods. Compounds 2, 3, 8, and 9 showed weak anti-inflammatory activities.     

New flavans,spirostanol sapogenins,and a pregnane genin from Tupistra chinensis and their cytotoxicity

Seven new compounds, including three new flavans [tupichinol A-C (1-3)], three new spirostanol sapogenins [tupichigenin D-F (4-6)], and one new pregnane genin [tupipregnenolone (7)], together with 18 known compounds, were isolated from the underground parts of Tupistra chinensis. The structures of the new compounds were elucidated by spectroscopic analysis and chemical evidence. The structures and relative stereochemistry of 1 and 9 were further confirmed by single-crystal X-ray crystallographic analysis. Compounds Delta(25(27))-pentrogenin, 10, and ranmogenin A showed 100%, 96%, and 80% inhibition, respectively, against human gastric tumor (NUGC) cells at a concentration of 50 microM. Delta(25(27))-pentrogenin showed 100% inhibition against human nasopharyngeal carcinoma (HONE-1) cells at a concentration of 50 microM.     

Labdane Diterpenoids from Marrubium globosum ssp. libanoticum

From the aerial parts of Marrubium globosum ssp. libanoticum, seven labdane diterpenoids were isolated. Three of them are new natural products [(13R)-9alpha,13alpha-epoxylabda-6beta(19),16(15)-diol dilactone (2), deacetylvitexilactone (7), marrulanic acid (8)], whereas the other four, namely, (13S)-9alpha,13alpha-epoxylabda-6beta(19),16(15)-diol dilactone (1), cyllenin A (3), 15-epi-cyllenin A (4), and marrulibanoside, are previously known compounds. The structures of 2, 7, and 8 were determined by spectroscopic and chemical methods.     

Inhibitory potential of three Yin-tonification herbal formulas on the activities of human major cytochrome P450 and UDP-glucuronosyltransferases isozymes in vitro

OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.     

Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities

Three new sesquiterpenes, (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (1), (2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2), and (5R)-2,6,9-humulatrien-5-ol-8-one (3), and two new flavonol glycosides, kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside) (4) and kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5), were isolated from the EtOAc-soluble fraction of the water extract of Zingiber aromaticum, along with 13 known compounds (6-18). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5) showed the most potent inhibitory activity (IC(50), 14.4 microM) on the metabolism mediated by CYP3A4, and kaempferol-3-O-methyl ether (14) inhibited CYP2D6 most potently (IC(50), 4.63 microM).     

Potent CYP3A4 inhibitory constituents of Piper cubeba

The EtOAc-soluble fraction of the water extract of Piper cubeba, having shown potent inhibitory activity on the metabolism mediated by CYP3A4, was subjected to activity-guided isolation to yield two new lignans, (8R,8'R)-4-hydroxycubebinone (1) and (8R,8'R,9'S)-5-methoxyclusin (2), and two new sesquiterpenes, (5 alpha,8 alpha)-2-oxo-1(10),3,7(11)-guaiatrien-12,8-olide (3) and (1 alpha,2 beta,5 alpha,8 alpha 10 alpha)-1,10-epoxy-2-hydroxy-3,7(11)-guaiadien-12,8-olide (4), along with 16 known compounds (5-20). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. The compounds (8R,8'R,9'S)-5-methoxyclusin (2), (-)-clusin (10), (-)-yatein (13), ethoxyclusin (15), and (-)-dihydroclusin (17), having one methylenedioxyphenyl moiety in their structures, showed very potent and selective inhibitory activity against CYP3A4 with IC(50) values (0.44-1.0 microM) identical to that of the positive control, ketoconazole (IC(50), 0.72 microM).     

Activity-guided fractionation of the leaves of Ormosia sumatrana using a proteasome inhibition assay

Activity-guided fractionation of a chloroform-soluble extract of the leaves of Ormosia sumatrana, using a proteasome inhibition assay, led to the isolation of a new A-type proanthocyanidin derivative, 3'-O-cinnamoylprocyanidin A-2 (1), and a new cerebroside, sumatranoside (2). The structures of these two isolates were determined as epicatechin-(2 beta-->O-->7',4 beta-->8')-epicatechin-3'-O-cinnamate (1) and 1-O-(beta-d-glucopyranosyl)-(2S,3S,4R)-2N-[(2'R)-2'-hydroxy-tetracosanoyl]-9Z-octadecene-1,3,4-triol (2), respectively, by spectroscopic and chemical methods. Sumatranoside (2) exhibited proteasome inhibitory activity with an IC(50) value of 30 microM.     

Microbial transformations of aryltetralone and aryltetralin lignans by Cunninghamella echinulata and Beauveria bassiana

Microbiological transformation of the aryltetralone lignan (-)-8'-epi-aristoligone (1) with Cunninghamella echinulata ATCC 10028B afforded two known natural lignans, (-)-holostyligone (3) and (-)-arisantetralone (4). Incubation of the aryltetralin lignan (-)-isogalbulin (2), obtained by chemical transformation of 1, with C. echinulata ATCC 10028B afforded the known lignan aryltetralol (5) and seven new metabolites, (-)-8-hydroxyisogalbulin (6), (-)-7-methoxyisogalbulin (7), (-)-4'-O-demethyl-8-hydroxyisogalbulin (8), (-)-7-methoxy-8-hydroxyisogalbulin (9), (-)-4'-O-demethyl-7-methoxyisogalbulin (10), (-)-4',5-O-didemethylcyclogalgravin (11), and (-)-4'-O-demethylcyclogalgravin (12). When 2 was subjected to biotransformation with Beauveria bassiana ATCC 7159, (-)-8-hydroxyisogalbulin (6) was the only isolable product. The structures of all new compounds were established by detailed analysis of their spectroscopic data.     

N-(jasmonoyl)tyrosine-derived compounds from flowers of broad beans (Vicia faba)

Two new amide-linked conjugates of jasmonic acid, N-[(3R,7R)-(-)-jasmonoyl]-(S)-dopa (3) and N-[(3R,7R)-(-)-jasmonoyl]-dopamine (5), were isolated in addition to the known compound N-[(3R,7R)-(-)-jasmonoyl]-(S)-tyrosine (2) from the methanolic extract of flowers of broad bean (Vicia faba). Their structures were proposed on the basis of spectroscopic data (LC-MS/MS) and chromatographic properties on reversed and chiral phases and confirmed by partial syntheses. Furthermore, tyrosine conjugates of two cucurbic acid isomers (7, 8) were detected and characterized by LC-MS. Crude enzyme preparations from flowers of V. faba hydroxylated both (+/-)-2 and N-[(3R,7R/3S,7S)-(-)-jasmonoyl]tyramine [(+/-)-4] to (+/-)-3 and (+/-)-5, respectively, suggesting a possible biosynthetic relationship. In addition, a commercial tyrosinase (mushroom) and a tyrosinase-containing extract from hairy roots of red beet exhibited the same catalytic properties, but with different substrate specificities. The conjugates (+/-)-2, (+/-)-3, (+/-)-4, and (+/-)-5 exhibited in a bioassay low activity to elicit alkaloid formation in comparison to free (+/-)-jasmonic acid [(+/-)-1].     

Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs

The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were explored in vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism‐based (irreversible) inhibition was assessed by time‐dependent and nicotinamide adenine dinucleotide phosphate‐dependent and reversible inhibition by Lineweaver–Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism‐based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism‐based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhibition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H‐bond and several Pi‐bond connections with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb–drug interactions. Tetrahydropalmatine and Ber should be considered for herb–drug interactions in clinical therapy until relevant clinical studies are available. Copyright © 2015 John Wiley & Sons, Ltd.     

Cerebrosides and tocopherol trimers from the seeds of Euryale ferox

Two new cerebrosides, ferocerebrosides A (1) [(2S,3R,4E,8E,2'R)-1-O-(beta-glucopyranosyl)-N-(2'-hydroxydocosanoyl)-4,8-sphingadienine] and B (2) [(2S,3R,4E,8E,2'R)-1-O-(beta-glucopyranosyl)-N-(2'-hydroxytetracosanoyl)-4,8-sphingadienine], two new tocopherol trimers, ferotocotrimers C (5) and D (6), and two known tocopherol trimers, IVb (3) and IVa (4), were isolated from the seeds of Euryale ferox. Their structures were determined on the basis of spectroscopic data, especially 1D and 2D NMR experiments. Compounds 1 and 2 showed cytotoxicity in the brine shrimp lethality bioassay, with LC50 values of 0.17 and 0.20 mM, respectively.     

Isolation and characterization of miscellaneous secondary metabolites of Deprea subtriflora

Two new C-18 norwithanolides based on a C(27) skeleton, subtrifloralactones K (1) and L (2), a new C-18 oxygenated withanolide, 13 beta-hydroxymethylsubtrifloralactone E (3), and a new alpha-ionone derivative, (+)-7 alpha,8 alpha-epoxyblumenol B (4), along with five known compounds, philadelphicalactone A (5), (2S,3S,4R)-2-[(2R)-2'-hydroxytetracosanoylamino]-1,3,4-octadecanetriol (6), trans-N-feruloyltyramine, cis-N-feruloyltyramine, and (S)-coriolic acid, were isolated from additional active fractions of the chloroform-soluble extract of Deprea subtriflora, using a quinone reductase (QR) induction assay as a monitor. The structures of compounds 1-4 were characterized by spectroscopic data interpretation. The potential cancer chemopreventive activities of all isolates in terms of their ability to induce QR activity with cultured Hepa 1c1c7 mouse hepatoma cells were evaluated.     

复方丹参方对大鼠心脏细胞色素P450酶的影响

目的 研究复方丹参方及其单味药对大鼠心脏细胞色素P450酶（CYPs）主要亚型的影响。方法 雄性SD大鼠随机分为5组,分别用复方丹参方 [0.32 g/(kg?d)]、丹参 [0.27 g/(kg?d)]、三七 [0.05 g/(kg?d)]、冰片 [0.003 g/(kg?d)] 或生理盐水连续ig诱导处理28 d,取各组大鼠心脏组织,利用Real Time荧光定量PCR技术检测各组大鼠心脏CYPs各亚型mRNA表达水平的变化。结果 与对照组比较,复方丹参方对大鼠心脏CYP1B1、CYP2B1、CYP2E1、CYP4A1和CYP4F4的mRNA表达有下调趋势（P＜0.05）。丹参对CYP1A1、CYP1B1、CYP2B1、CYP2C11、CYP2E1、CYP2J3、CYP4A1、CYP4F4和CYP4F5的mRNA表达有下调趋势（P＜0.05、0.01）,而对CYP4A3、CYP4F1和CYP4F6的mRNA表达有上调趋势（P＜0.05）。三七对CYP1A1、CYP1B1、CYP2B1、CYP2C11、CYP2E1、CYP2J3、CYP4A1、CYP4A3、CYP4F4、CYP4F5和CYP4F6的mRNA表达均有不同程度的抑制趋势（P＜0.05、0.01）。冰片对CYP1A1、CYP1B1、CYP2B1、CYP2C11、CYP4A1和CYP4F4的mRNA表达有下调作用（P＜0.01）。结论 复方丹参方全方对心脏CYPs 亚型mRNA表达影响弱于方中各单味药对CYPs的影响,显示复方对CYPs影响可能是各单味药作用的综合和叠加,同时全方及单味药对CYP2家族和CYP4家族的影响显示其对心脏均有双向调节作用。     

Lignans and their degraded derivatives from Sarcostemma acidum

Four lignans, sacidumlignans A-D (1-4), and two degraded lignan derivatives, sacidumols A (5) and B (6), along with four known compounds, (+)-pinoresinol, 9alpha-hydroxypinoresinol, perforatic acid, and peucenine-7-O-methyl ether, were isolated from the ethanolic extract of the whole plant of Sarcostemma acidum. The structures and relative configuration of these new compounds were elucidated on the basis of spectroscopic and chemical data, especially 2D NMR techniques. Sacidumlignan D (4) was assigned as a rearranged tetrahydrofuran lignan with an unprecedented skeleton. Sacidumlignan A (1) showed moderate antimicrobial activities against two Gram-positive bacteria in vitro.     

Antitubercular chromones and flavonoids from Pisonia aculeata

Three new chromones, pisonins A (1), B (2), and D (4), two new flavonoids, pisonivanone [(2S)-5,7,2'-trihydroxy-8-methylflavanone] (7) and pisonivanol [(2R,3R)-3,7-dihydroxy-5,6-dimethoxyflavanone] (8), one new isoflavonoid, pisonianone (5,7,2'-trihydroxy-6-methoxy-8-methylisoflavone) (9), and five compounds first isolated from nature, namely, pisonins C (3), E (5), and F (6), pisoniamide (10), and pisonolic acid (11), together with 18 known compounds have been isolated from the methanol extract of the combined stem and root of Pisonia aculeata. Among these isolates, 2, 7, 14, 16, and 19 exhibited antitubercular activities (MICs≤50.0 μg/mL) against Mycobacterium tuberculosis H37Rv in vitro.     

Flavonoid, iridoid, and lignan glycosides from Putoria calabrica

From the aerial parts of Putoria calabrica, two new flavonol triglycosides were isolated and their structures were elucidated as quercetin-3-O-[alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside]-7-O-beta-D-glucopyranoside (1, calabricoside A) and quercetin-3-O-[4' "-O-caffeoyl-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside]-7-O-beta-D-glucopyranoside (2, calabricoside B). Additionally, seven iridoid and three lignan glycosides were isolated and characterized. Radical scavenging activities of all compounds were determined by quantifying their effects on luminol-enhanced chemiluminescence in formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated human polymorphonuclear neutrophils (PMNs). Calabricoside A and B showed strong radical scavenging activity with IC(50) values of 0.25 and 0.3 microM, respectively.     

New sphingosines from a gorgonian, Pseudopterogorgia australiensis Ridley, of the Indian Ocean

Two new sphingosines, (2S,3R)-2-(docosanoyl amino)nonadecane-1,3-diol (1) and (2S,3S,4R)-2-[(2'R)-2'-hydroxynonadecanoylamino]nonadecane-1,3,4-triol (3), along with the known (2S,3R,4E)-2-(heptadecanoylamino)octadec-4-ene-1,3-diol, have been isolated from Pseudopterogorgia australiensis, of the Indian Ocean. The structures were deduced from spectral and chemical methods. Compounds 1-3 showed moderate antibacterial activity.