Abietane diterpenoids from the cones of Larix kaempferi and their inhibitory effects on Epstein-Barr virus activation

Four known (1-3, 8) and four new abietane diterpenes, 15-hydroxy-8alpha,14alpha,12alpha,13alpha-diepoxyabietan-18-oic acid (4), 7alpha,8alpha,13beta,14beta-diepoxyabietan-18-oic acid (5), 18-nor-abieta-8,11,13-triene-4alpha,7alpha,15-triol (6), and abieta-8,11,13-triene-7alpha,15,18-triol (7) were isolated from the CHCl3 extract of the cones of Larix koempferi. A known compound, 13,14-seco-13,14-dioxoabiet-13-en-18-oic acid (8) was isolated from natural sources for the first time. Their structures were determined by chemical and spectroscopic methods including 1D and 2D NMR techniques. The absolute stereostructure of 5 was determined by X-ray crystallographic analysis. The inhibitory effects of these compounds on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), were examined as a primary screening for antitumor promotors.     

Terpenoids and steroids from several euphorbiaceae and pinaceae plants]

During the course of a search for biologically active constituents from unexamined plant sources, several biogenetically interesting new di- and tri-terpenes and steroids were isolated from several weeds and shrubs of Euphorbiaceae and the bark, leaves and cones of several Pinaceae trees which had been treated as wastes in the forestry industry. Euphorbia supina contained 3,4-seco-5 alpha- and 5 beta-adian-4(23)-ene-3,5-diols and related oxides, oxygenated fern-8-en-3 beta-ols named supinenolones A-E and unusually migrated oxyfernanes having (9S)- and (9R)-7(8-->9)abeo-9-D:C-friedo-B':A'-neogammacerane skeletons named spirosupinane and neospirosupinane, while E. chamaesyce contained 3,4-seco-oleana-4(23), 18-dien-3-oic acid, 3,4-seco-8 beta H-ferna-4(23),9(11)-dien-3-oic acid and two oxygenated obtusifoliols. The bark of Phyllanthus flexuosus (Euphorbiaceae) contained 11 beta-hydroxy-D:A-friedo-olean-1-en-3-one, lup-20(29)-ene-3 beta, 15 alpha-diol, olean-12-ene-3 beta,15 alpha-diol and olean-12-ene-3 beta,15 alpha,24-triol together with trichadenic acid B for which we revised the structure to 3 beta-hydroxy-D:A-friedo-oleanan-27-oic acid. Two 26-nor-D:A-friedo-olean-14-enes were isolated from P. watsonii. Regarding Pinaceae trees, an unusually migrated abieslactone [(3R, 7S, 9R, 23R)-7-hydroxy-3-methoxy-8-oxo-7(8-->9)abeo-lanost-24-eno-26,23-lactone], named spiroveitchionolide, was isolated from the bark of Abies species, besides nine abieslactone analogues. Two pairs of unusually migrated serratanes, piceanonols A and B and jezananals A and B having novel skeletal systems of 14(13-->12) abeo- and 16(15-->14) abeo-serratanes named piceanane and jezanane, respectively, were also isolated from the stem bark of Picea species, besides three 14 beta,15 beta-epoxyserratanes and two 13 alpha,14 alpha-epoxyserratanes. The leaves of Larix kaempferi contained two deformed abietanes named karamatsuic acid (9,10-seco-9,10 alpha-epoxyabieta-8,11,13-trien-18-oic acid) and larikaempferic acid [9 alpha,13 alpha-epoxy-8-oxo-9(8-->7)abeo-7 beta-abietan-18-oic acid], as well as the cones to contain 8 alpha,12 alpha-epidioxy-15-hydroxyabiet-13-en-18-oic acid, three diepoxy-abietan-18-oic acids and two new dehydroabietic acid analogues. Several of the above compounds exhibited inhibitory effects against tumor-promoting and DNA topoisomerase II activities.     

番荔枝化学成分研究

从番荔枝(Annona squamosa)中分离得到12个化合物,分别鉴定为liriodenine(AS—1),穆坪马兜铃酰胺(moupinamide,AS-2),-(-)-kauran-16α-01-19-oic acid(AS-3),16β,17-dihydroxy-(-)-kauran-19-oic acid(AS-4),anonaine(AS-5),16α,17-dihydroxy-(-)-kauran-19-oic acid(AS-6),(-)-isokaur-15(16)-en-17,19-dioic acid(AS-7),番荔枝酰胺squamosamide(AS-8),16α-methoxy-(-)kauran-19-oicacid(AS-9),sachanoic acid(AS-10),(-)-kauran-19-al-17-oic acid(AS-11),daucosterol(AS-12)。其中,番荔枝酰胺(AS-8)是新化合物,AS-9是第一次从植物中得到的天然产物。     

New beyerane and isopimarane diterpenoids from Rhizophora mucronata

Chemical examination of the ethyl acetate extract of the roots of Rhizophora mucronata collected from Mangalore Coast resulted in the isolation of three more new diterpenoids, rhizophorins C-E (1-3) in addition to the two, rhizophorin A, (6R,11S,13S)-6,11,13-trihydroxy-2,3-seco-14-labden-2,8-olid-3-oic acid, and rhizophorin B, ent-3beta,20-epoxy-3alpha,18-dihydroxy-15-beyerene, recently reported. The structures of the new diterpenoids have been elucidated by a study of their physical and spectral data as 17-hydroxybeyer-15-en-3-one (1), 3beta,17-diacetoxy-15-beyeren-2-one (2) and 3beta,6alpha-diacetoxy-8(14),15-isopimaradien-2-one (3).     

Functional pharmacology of human prostanoid EP2 and EP4 receptors

Prostanoid EP(2) and EP(4) receptor-mediated responses are difficult to distinguish pharmacologically because of the lack of potent, selective antagonists. We describe systematic agonist fingerprints for recombinant human prostanoid EP(2) and EP(4) receptors expressed in CHO and HEK293 cells, respectively. The rank orders of potency of endogenous prostaglandins were: prostanoid EP(2) receptors: prostaglandin E(2)>prostaglandin D(2)=prostaglandin F(2alpha)>prostaglandin I(2); prostanoid EP(4) receptors: prostaglandin E(2)>prostaglandin I(2)>prostaglandin D(2)=prostaglandin F(2alpha). Butaprost free acid (9-oxo-11alpha,16R-dihydroxy-17-cyclobutyl-prost-13E-en-1-oic acid) behaved as a highly selective partial agonist at prostanoid EP(2) receptors while butaprost methyl ester elicited small, low potency responses. The prostanoid EP(1) and EP(3) receptor agonists misoprostol (9-oxo-11alpha,16-dihydroxy-16-methyl-prost-13E-en-1-oic acid, methyl ester), sulprostone (N-(methylsulphonyl)-9-oxo-11alpha,15R-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-5Z,13E-dien-1-amide), and GR63799X ([1R-[1alpha(Z),2beta(R*),3alpha]-(-)-4-benzoylamino)phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5-oxocyclopentyl]-4-heptenoate), and the prostanoid DP receptor agonist BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-hydropropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), activated both prostanoid EP(2) and EP(4) receptors. Prostaglandin I(2), iloprost (6,9alpha-methylene-11alpha,15S-dihydroxy-16-methyl-prosta-5E,13E-dien-18-yn-1-oic acid, trometamol salt) and cicaprost (5-[(E)-(1S, 5S, 6S, 7R)-7-hydroxy-6-[(3S, 4S)-3-hydroxy-4-methylnona-1,6-diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid; ZK96480) were full agonists at prostanoid EP(4) receptors. Key differentiating agonists are: butaprost FA, 16,16-dimethyl-prostaglandin E(2), 19-(R)-hydroxy prostaglandin E(2), misoprostol, BW245C, prostaglandin F(2alpha) and prostaglandin D(2).     

Kaurane-type diterpene glycoside from the stem bark of Acanthopanax trifoliatus

A new diterpene glycoside, acantrifoside D ( 1), as well as three known diterpenes (2 - 4) were isolated from the stem bark of Acanthopanax trifoliatus from Vietnam. Based on 1D and 2D NMR spectroscopic data, their chemical structures were determined to be 16alpha,17-dihydroxy- ent-kauran-19-oic acid 16- O-beta- D-glucopyranoside 19- O-beta- D-glucopyranosyl ester (1), 16alpha H,17-isovalerate- ent-kauran-19-oic acid (2), ent-kaur-16-en-19-oic acid ( 3), and ent-pimara-8(14),15-dien-19-oic acid (4). Compounds 2 - 4 had strong inhibitory effects against COX-1 in an in vitro assay, with IC50 values of 0.21, 0.15 and 0.19 mM, respectively.     

向日葵二萜化学成分及其细胞毒活性研究

为了研究向日葵(Helianthus annuus L.)的生物活性成分。本文采用色谱法系统研究向日葵的化学成分，根据波谱学分析鉴定了化合物的结构，用MTT法评价其细胞毒活性。从成熟的向日葵花盘中分离鉴定了11个化合物，分别为：对映贝壳杉-2α,16α-二醇(1)，对映贝壳杉-15α,16α-环氧-17-醛-19-酸(2)，对映贝壳杉-16β-醇(3)，phyllocladan-16β-ol (4)，ent-atisan-16α-ol (5)，15-羟基-对映贝壳杉-16-烯-19酸(6)，对映贝壳-15-当归酰氧基-16-烯-19-酸(7)，对映贝壳杉-16-烯-19酸(8)，对映贝壳杉-17-羟基-15-烯-19酸(9)，对映贝壳杉-16β，17-二羟基-19酸(10)和ciliaric acid (11)。其中化合物1和2为新化合物，部分化合物显示一定的细胞毒活性。     

Anti-tumor-promoting rearranged abietane diterpenes from the leaves of Larix kaempferi

Two novel rearranged abietane-type diterpene acids, karamatsuic acid (1) and larikaempferic acid (2) were isolated as their corresponding methyl esters, 1a and 2a, from the leaves of Larix kaempferi (Lamb.) Carr. Their structures were established as 9,10 alpha-epoxy-9,10-seco-abieta-8,11,13-trien-18-oic acid and 9 alpha,13 alpha-epoxy-8-oxo-9(8-->7)abeo-7 beta H-abietan-18-oic acid, respectively, by spectral evidence. Compounds 1a, 2a and 12,15-dihydroxydehydroabietic acid (3) exhibited potent inhibitory effects against 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells.     

Chemical constituents of Nouelia insignis Franch

Two new diterpenes and ent-15alpha-hydroxykaur-16-en-19-oic acid 11,12-acetonide (3), together with 23 known compounds were isolated from the dried aerial parts of Nouelia insignis Franch. The structures of new compounds were determined to be ent-14beta,15alpha-dihydroxykaur-16-en-19-oic acid (1), ent-14beta-hydroxy-15-oxokaur-16-en-19-oic acid (2) on the basis of spectral and chemical evidence. The structure of ent-11alpha,16alpha-epoxy-15alpha-hydroxy-16S-kaur-19-oic acid (4) was confirmed by X-ray crystallographic analysis.     

Inhibitory Constituents against Cyclooxygenases fromAralia cordata Thunb

Seven diterpenes, four polyacetylenes, a lipid glycerol, and two sterols were isolated from the methylene chloride fraction of the root of Aralia cordata. Their chemical structures were determined as (-)-pimara-8(14),15-dien-19-oic acid (2), pimaric acid (3), (-)-kaur-16-en-19-oic acid (4), 17-hydroxy-ent-kaur-15-en-19-oic acid (9), 7alpha-hydroxy-(-)-pimara-8(14),15-dien-19-oic acid (10), 16alpha,17-dihydroxy-(-)-kauran-19-oic acid (11), 16-hydroxy-17-isovaleroyloxy-ent-kauran-19-oic acid (12), falcarindiol (5), dehydrofalcarindiol (6), dehydrofalcarindiol-8-acetate (7), falcarindiol-8-acetate (8), alpha-mono palmitin (13), stigmasterol (1), and daucosterol (14) by the spectral evidences. These compounds were tested with COX-1 and COX-2 inhibition assays. This study found that compounds 2, 4, 5, 6, 7, 8, and 10 inhibited COX-1 dependent conversion of the exogenous arachidonic acid to PGE2 in a dose-dependent manner with IC50 values of 134.2 microM, 121.6 microM, 170 microM, 50.4 microM, 11.7 microM, 99.6 microM, and 69.6 microM, respectively. But, most of these compounds weakly inhibited COX-2 dependent PGE2 generation. Among them, only compound 4 showed relatively significant inhibitory activity (IC50: 127.6 microM).     

Hydroxylation and glucosidation of ent-16beta-Hydroxybeyeran-19-oic acid by Bacillus megaterium and Aspergillus niger

ent-16beta-Hydroxybeyeran-19-oic acid ( 1) has potential antihypertensive activity. To obtain novel and more-effective compounds, 1 was incubated with Bacillus megaterium ATCC 14 581 and Aspergillus niger CCRC 32 720. The structures of the metabolites were determined by HR-FAB-MS, 1D- and 2D-NMR spectral data, and enzymatic hydrolysis. Bacillus megaterium hydroxylated and glucosidated 1 to yield ent-7alpha,16beta-dihydroxybeyeran-19-oic acid ( 2), ent-16beta-hydroxybeyeran-19-oic acid alpha- D-glucopyranosyl ester ( 3), and ent-7alpha,16beta-dihydroxybeyeran-19-oic acid alpha- D-glucopyranosyl ester ( 4). Aspergillus niger hydroxylated 1 to yield ent-1beta,7alpha,16beta-trihydroxybeyeran-19-oic acid ( 5) and ent-1beta,7alpha-dihydroxy-16-oxobeyeran-19-oic acid ( 6). Metabolites 3 - 5 were characterized as new compounds. In addition, 2, 3, 5, and 6 were tested for antihypertensive effects, and we found that 5 and 6 were more potent than the parent compound 1.     

Antioxidative 7-oxodehydropodocarpane-type trinorditerpenes from the bark of Taiwania cryptomerioides

Five new 7-oxopodocarpane-type trinorditerpenes together with 1beta,13,14-trihydroxy-8,11,13-podocarpatrien-7-one ( 1) were isolated from the bark of Taiwania cryptomerioides. By using NMR and other spectral methods, the structures of five new compounds, 14-hydroxy-13-methoxy-8,11,13-podocarpatriene-3,7-dione ( 2), 1beta,14-dihydroxy-13-methoxy-8,11,13-podocarpatrien-7-one ( 3), 13,14-dihydroxy-8,11,13-podocarpatriene-3,7-dione ( 4), 3beta,13,14-trihydroxy-8,11,13-podocarpatrien-7-one ( 5), and 1beta,13,14-trihydroxy-8,11,13-podocarpatriene-2,7-dione ( 6), were elucidated. Compounds 1, 4, 5, and 6 exhibited strong antioxidative activity.     

Anti-lymphangiogenic diterpenes from the bark of Calocedrus macrolepis var. formosana

Eight new diterpenes, 6α,7β-dihydroxyferruginol (1), 6α,7α-dihydroxyferruginol (2), 6α-hydroxyhinokiol (3), 4α-hydroxy-7-oxo-18-norabieta-8,11,13-trien-4α-ol (4a), 15,16-dehydrosugiol (5), 7-methoxy-6,7-secoabieta-8,11,13-triene-6,12-diol (6), 7α-acetoxyabieta-8,12-diene-11,14-dione (7), 7α-butyloxyethyloxyabieta-8,12-diene-11,14-dione (8), along with four known compounds, 6,7-dehydroferruginol (9), 12-hydroxy-6,7-secoabieta-8,11,13-triene-6,7-dial (10), 7α-11-dihydroxy-12-methoxy-8,11,13-abietatriene (11), and 11,14-dihydroxy-8,11,13-abietatrien-7-one (12) were successfully isolated from the bark of Calocedrus macrolepis var. formosana. The structures of all isolates were elucidated by physical data (appearance, UV, IR, optical rotation) and spectroscopic data (1D, 2D NMR, and HREIMS). Compounds 9, 10, 11, and 12 showed promising growth-inhibitory effect on human lymphatic endothelial cells (LECs). Among these compounds, compound 10 exerted the most potent anti-lymphangiogenesis property by suppressing cell growth and tube formation of LECs. In conclusion, the results revealed the anti-lymphangiogenic potentials of Formosan C. macrolepis var. formosana.     

Aromatase inhibitory activities of standishinal and the diterpenoids from the bark of Thuja standishii

The absolute stereostructure of a novel skeletal diterpene, standishinal (1), from the bark of Thuja standishii was confirmed by X-ray crystallographic analyses of 1 and its p-bromobenzoate derivative. Aromatase inhibitory activities of standishinal, eight known diterpenes, totarol, 12-methoxyabieta-8,11,13-trien-11-ol, 12-hydroxy-6,7-seco-abieta-8,11,13-triene-6,7-dial, trans-communic acid, labda-8(17),13-dien-12 R,15-olid-19-oic acid, 12 S-hydroxylabda-8(17),13(16),14-trien-19-oic acid, 13-oxo-15,16-dinorlabda-8(17),11 E-dien-19-oic acid and 14-oxo-15-norlabda-8 (17),12 E-dien-19-oic acid from the plant, and four synthetic analogs were evaluated using a recombinant human aromatase. Among them, standishinal and its diacetate derivative had significant inhibitory activities.     

豨莶脂溶性成分的研究

从豨莶(Siegesbeckia orientalis L.)的地上部分,分离出八个化合物,其中I和I根据理化性质和光谱数据确定其结构为ent-17-acetoxy-18-isobutyryloxy-16(α)-kauran-19-oicacid(I)和ent-17-ethoxy-16(α)-kauran-19-oicacid(II),均为新化合物,分别被命为豨莶酯酸(siegesesteric acid,I)和豨莶醚酸(siegesetheric acid,I)。其余化合物分别鉴定为腺梗豨莶萜醇酸(ent-16β,17-dihydroxy-kauran-19-oicacid,II),奇任醇(kirenol,IV,β-谷甾醇葡萄糖甙(β-sitosterolglucoside,V),二十一醇(heneicosanol,VI),花生酸甲酯(methyl arachidate,VII)和β-谷甾醇(β-sitosterol,VII)。除奇任醇和β-谷甾醇外,均为首次从该植物中分得。     

New terpenes from Salvia palaestina Benth. and Salvia syriaca L. growing wild in Jordan

The novel seco-ursane-type triterpenoid 3β,11α-dihydroxy-17,22-seco-17(28), 12-ursadien-22-oic acid (1) was isolated for the first time from a natural source from two Salvia species growing wild in Jordan, Salvia palaestina Benth. and Salvia syrica L. In addition to compound 1, S. syriaca afforded a new sesquiterpene named syriacine (2). S. palaestina also afforded 15 other known compounds, 6 of which are isolated for the first time from the plant, and these include velutin, hyptadienic acid, cirsilineol, 2α,3β-dihydroxyurs-12-en-28-oic acid, 2α,3α-dihydroxy-24-nor-4(23),12-oleanan-28-oic acid, and 2α,3β,24-trihydroxyurs-12-en-28-oic acid. S. syriaca also afforded 16 other known compounds, 7 of which are isolated for the first time from the plant. These are 1α,3α-dihydroxyolean-9(11),12-diene, maslinic acid, 2α,3β,24-trihydroxyolean-12-en-28-oic acid, 11-oxo-oleanolic acid, 11-oxo-ursolic acid, poriferast-5-en-3,7-diol, and pectolinangenin.     

Bioactive triterpenoids from Symplocos chinensis

A new triterpenoid, 2beta,3beta,19alpha,24-tetrahydroxy-23-norurs-12-en-28-oic acid (4), together with three known triterpenoids 3-oxo-19alpha,23,24-trihydroxyurs-12-en-28-oic acid (1), 2alpha,3beta,19alpha,23-tetrahydroxyurs-12-en-28-oic acid (2), 2alpha,3alpha,19alpha,23-tetrahydroxyurs-12-en-28-oic acid (3), was isolated from the roots of Symplocos chinensis. The new triterpenoid shows significant cytotoxic activity against B16 and BGC-823 cells.     

Inhibitory effects of ent-kauranes from the stems of Annona squamosa on superoxide anion generation by human neutrophils

Eleven ent-kauranes, isolated from the fresh stems of Annona squamosa L. (Annonaceae), were subjected to assays on the generation of superoxide anion (O2.--) by human neutrophils. Except for ent-kaur-16-en-19-oic acid, 16beta,17-dihydroxy- ent-kauran-19-al, and 16alpha,17-dihydroxy -ent-kauran-19-al, all ent-kauranes showed significant inhibitory effect on O2.-- generation in response to formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP/CB). In contrast, phorbol myristate acetate (PMA)-induced O2.-- generation was not suppressed by any ent-kauranes. Especially, ent-kaur-16-en-19-oic acid could significantly increase O2.-- production. The structure-activity relationship of these compounds is also discussed herein. Furthermore, the effect of ent-kauranes on nitric oxide generation by NR8383 macrophages in response to lipopolysaccharide (LPS) was examined. None of the compounds showed an inhibitory effect on nitric oxide generation.     

Diterpenoids from the Chinese herb Caryopteris terniflora and their antibacterial and antitumor activity

Two ent-kaurene type diterpenoids, diterpenoids A (1) and B (2) were isolated from the Chinese herb Caryopteris terniflora and defined as ent-7beta, 11alpha,14-trihydroxy-18-aldehyde-11beta-20-epoxy-kaur-16-en15-one and ent-7beta,14-dihydroxy-11alpha-methoxy-18-aldehyde-11beta-20-epoxy-kaur-16-en-15-one respectively. Compounds 1 and 2 showed significant antibacterial and antitumour activity.     

Search for constituents with neurotrophic factor-potentiating activity from the medicinal plants of paraguay and Thailand

20 medicinal plants of Paraguay and 3 medicinal plants of Thailand were examined on nerve growth factor (NGF)-potentiating activities in PC12D cells. The trail results demonstrated that the methanol extracts of four plants, Verbena littoralis, Scoparia dulcis, Artemisia absinthium and Garcinia xanthochymus, markedly enhanced the neurite outgrowth induced by NGF from PC12D cells. Furthermore, utilizing the bioactivity-guided separation we successfully isolated 32, 4 and 5 constituents from V. littoralis, S. dulcis and G. xanthochymus, respectively, including nine iridoid and iridoid glucosides (1-9), two dihydrochalcone dimers (10 and 11), two flavonoids and three flavonoid glycosides (12-16), two sterols (17 and 18), ten triterpenoids (19-28), five xanthones (29-33), one naphthoquinone (34), one benzenepropanamide (35), four phenylethanoid glycosides (36-39) and two other compounds (40 and 41). Among which, 15 compounds (1-4, 10-11, 14-18, 29-31 and 34) were new natural products. The results of pharmacological trails verified that littoralisone (1), gelsemiol (5), 7a-hydroxysemperoside aglucone (6), verbenachalcone (10), littorachalcone (11), stigmast-5-ene 3beta,7alpha,22alpha-triol (18), ursolic acid (19), 3beta-hydroxyurs-11-en-28,13beta-olide (24), oleanolic acid (25), 2alpha,3beta-dihydroxyolean-12-en-28-oic acid (26), 1,4,5,6-tetrahydroxy-7,8-di(3-methylbut-2-enyl)xanthone (29), 1,2,6-trihydroxy-5-methoxy-7-(3-methylbut-2-enyl)xanthone (30), 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (31), 12b-hydroxy-des-D-garcigerrin A (32), garciniaxanthone E (33) and (4R)-4,9-dihydroxy-8-methoxy-alpha-lapachone (34) elicited marked enhancement of NGF-mediated neurite outgrowth in PC12D cells. These substances may contribute to the basic study and the medicinal development for the neurodegenerative disorder.