Non-glycosidic iridoids from Cymbaria mongolica

Six non-glycosidic iridoids, i.e. (1R,4S,4aS,7S,7aS)-7-hydroxyl-4-hydroxy- methyl-7-methyl-1-methoxyl-1,4,4a,7a-tetrahydrocyclopenta[e]pyran-3-one (1), (1S,4R,4aS,7S,7aS)-7-hydroxyl-4-hydroxymethyl-7-methyl-1-methoxyl-1,4,4a,7a-tetrahydrocyclopenta[e]pyran-3-one (2), (1R,4R,4aS,7S,7aS)-7-hydroxyl-4-hydroxy-methyl-7-methyl-1-methoxyl-1,4,4a,7a-tetrahydrocyclopenta[e]pyran-3-one (3), (1R, 4R, 4aS, 7aS)-4,7-dihydroxymethyl-1-methoxyl-1,4,4a,7a-tetrahydrocyclopenta-6-ene[e]pyran-3-one (4), (1R, 4R, 4aS, 7aS)-4,7-dihydroxymethyl-1-hydroxyl-1,4,4a, 7a-tetrahydrocyclopenta-6-ene[e]pyran-3-one (5), (1R, 4S, 4aS, 7aS)-4,7-dihydroxy-methyl-1-methoxyl-1,4,4a,7a-tetrahydrocyclopenta-6-ene[e]pyran-3-one (6), as well as five known non-glycosidic iridoids mussaenin A (7), gardendiol (8), isoboonein (9), 4-epi-alyxialactone (10) and rehmaglutin D (11) have been isolated from the Chinese medicinal plant Cymbaria mongolica. Their structures were elucidated by spectroscopic methods. These compounds exhibit significant antitumor and antibacterial activity.     

Synthesis and Pseudomonas lipase inhibition study of stereoisomers of decahydro-2-naphthyl-N-n-butylcarbamate

(2S,4aR,8aS)-Cis,cis-, (2R,4aS,8aR)-cis,cis-, rac-cis,cis-, and rac-trans,cis-decahydro-2-naphthyl-N-n-butylcarbamates are synthesized from condensation of (2S,4aR,8aS)-cis,cis-, (2R,4aS,8aR)-cis,cis-, rac-cis,cis-, and rac-trans,cisdecahydro- 2-naphthols, respectively, with n-butyl isocyanate in the presence of triethylamine in dichloromethane. Optically pure (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)-cis,cis-decahydro-2-naphthols are resolved by the porcine pancreatic lipase- catalyzed acetylation of decahydro-2-naphthols with vinyl acetate in t-butyl methyl ether. Absolute configurations of (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)- cis,cis-decahydro-2-naphthols are determined from the 1?F NMR spectra of their Mosher's ester derivatives. (2S,4aR,8aR)-Trans,cis- and (2R,4aS,8aS)-trans,cis-decahydro-2-naphthols can't be resolved from the porcine pancreatic lipase-catalyzed acetylation of decahydro-2-naphthols with vinyl acetate in t-butyl methyl ether. For the inhibitory potency of Pseudomonas lipase, (2S,4aR,8aS)-cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate is 3.5 times more potent than (2R,4aS,8aR)-cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate; racemic cis,cis-decahydro- 2-naphthyl-N-n-butylcarbamate is about the same with trans,cis-decahydro-2-naphthyl-N-n-butylcarbamate. These inhibitors also show similar effects on porcine pancreatic lipase.     

Stereo-specific inhibition of acetyl- and butyryl-cholinesterases by enantiomers of cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate

Enantiomers of cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate show stereo-specific inhibition for acetylcholinesterase and butyrylcholinesterase. For both inhibition reaction, (2S,4aR,8aS)-cis,cis-decahydro-2-naphthyl-N-n- butylcarbamate is more potent than (2R,4aS,8aR)-cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate. Optically pure (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)-cis,cis-decahydro-2-naphthols are resolved by the porcine pancreatic lipase-catalyzed acetylation of decahydro-2-naphthols with vinyl acetate. Absolute configurations and the enantiomeric excess values of (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)-cis,cis-decahydro-2-naphthols are determined from the (19)F NMR spectra of their Mosher's ester derivatives. We fail to resolve (2S,4aR,8aR)- and (2R,4aS,8aS)-trans,cis-decahydro-2-naphthols from the porcine pancreatic lipase-catalyzed acetylation of decahydro-2-naphthols with vinyl acetate.     

Phenolic glycosides from Kaempferia parviflora

Three phenolic glycosides were isolated together with two known flavonol glycosides from the H2O-soluble fraction of rhizomes of Kaempferia parviflora. Their structures were determined to be rel-(5aS,10bS)-5a,10b-dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[b]indeno[1,2-d]furan-6-one 5a-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-d-glucopyranoside] (1), its rel-5aS,10bR isomer (2), and (2R,3S,4S)-3-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-d-glucopyranosyl]-3'-O-methyl-ent-epicatechin-(2alpha-->O-->3,4alpha-->4)-(5aS,10bS)-5a,10b-dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[b]indeno[1,2-d]furan-6-one 5a-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside] (3). The structures were elucidated on the basis of analyses of chemical and spectroscopic evidence.     

Characterisation and X-ray crystallography of products from the Bucherer-Bergs reaction of methyl 2,3-O-isopropylidene-alpha-D-lyxo-pentodialdo-1,4-furanoside

Methyl 2,3-O-isopropylidene-alpha-D-mannofuranosidurononitrile [alternative name: methyl (5R)-5-C-cyano-2,3-O-isopropylidene-alpha-D-lyxofuranoside] (2), methyl 2,3-O-isopropylidene-alpha-D-mannofuranosiduronamide [methyl (5S)-5-C-carbamoyl-2,3-O-isopropylidene-alpha-D-lyxofuranoside; methyl (5S)-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosiduronamide] (3), methyl 2,3-O-isopropylidene-alpha-D-mannofuranosiduronic acid [methyl (5S)-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosiduronic acid] (4), methyl 5-deoxy-2,3-O-isopropylidene-5-ureido-beta-L-gulofuranosiduronamide [methyl (5R)-5-deoxy-2,3-O-isopropylidene-5-ureido-alpha-D-lyxo-hexofuranosiduronamide (5), and (4S,5S,6R)-5,6-dihydro-6-hydroxy-4,5-isopropylidenedioxy-4H-pyrido[2,1-e]imidazolidine-2',4'-dione [IUPAC name: (3aS,4R,8aS)-4-hydroxy-2,2-dimethyl-3a,8a-dihydro-4H-1,3-dioxa-4a,6-diaza-s-indacene-5,7-dione] (6), instead of the expected hydantoin derivative, were obtained from the Bucherer-Bergs reaction of methyl 2,3-O-isopropylidene-alpha-D-lyxo-pentodialdo-1,4-furanoside (1). The structure of 6 was deduced from NMR and mass spectral data and confirmed by X-ray crystallography. The configuration at C-5 in 2-5 was confirmed by establishing the 5S configuration of 3 by X-ray crystallography. Conformations of the six- and five-membered rings in 3 and 6 are also discussed.     

Studies on the synthesis of safflomin-A, a yellow pigment in safflower petals: oxidation of 3-C-beta-d-glucopyranosyl-5-methylphloroacetophenone

The direct C-glycosylation of methylphloroacetophenone 8 with d-glucose gave C-beta-d-glucopyranosylmethylphloroacetophenone (7) in 65% yield, which, on oxidation in the presence of small amount of pyridine under an oxygen atmosphere afforded the quinone 9, oxidized at the methylated position of the benzene ring as a pair of diastereomers in 27% yield. A detailed NMR analysis and a comparison of the UV-vis and CD spectra of their acetates indicated that the structure and stereochemistry of 9 was (1R,1'S,2R,3S,3aS,5R and 1R,1'S,2R,3S,3aS,5S)-7-acetyl-2-(1',2'-dihydroxyethyl)-5-methyl-3,5,6-trihydroxy-8-oxofuro[3,2-d]benzo[b]furan.     

蚜虫性信息素的田间引诱蚜虫试验

据报道蚜虫的性信息素的主要成分是（＋）－（４ａＳ,７Ｓ,７ａＲ）－荆芥内醌（１）和（＋）－（１Ｒ,４ａＳ,７Ｓ,７ａＲ）＝荆芥醇（Ⅱ）。应用这两种物质进行引诱雄性蚜的田间实验,取得了良好的效果,初步获得了应用于田间的合适的配比及使用的时间。     

卵叶娃儿藤中的抗癌活性生物碱

从卵叶娃儿藤(Tylophora ovata (Lindl.) Hook. ex Steud.)根中分离得到 4个菲骈吲哚里西丁类生物碱,分别为tylophoridicine A (1)、娃儿藤宁(2)、氧甲基娃儿藤定(3)和娃儿藤定(4).经波谱分析并结合化学方法鉴定,其结构分别为:(13aR)-6-羟基-3,7-二甲氧基菲骈吲哚里西丁、 (13aS ,14R)-14-羟基-3,6,7-三甲氧基-菲骈吲哚里西丁、(13aS, 14S)-14-羟基-3,6,7-三甲氧基-菲骈吲哚里西丁和(13 aS,14S)-6,14-二羟基-3,7-二甲氧基-菲骈吲哚里西丁.化合物1为新化合物,化合物2-4为首次从该植物得到的化合物.经药理筛选,化合物1、3和4显示很强的抗癌活性.     

Recycling and resensitization of the neurokinin 1 receptor. Influence of agonist concentration and Rab GTPases

Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration. High SP (10 nM) induced translocation of the NK1R and beta-arrestin 1 to perinuclear sorting endosomes containing Rab5a, where NK1R remained for >60 min. Low SP (1 nM) induced translocation of the NK1R to early endosomes located immediately beneath the plasma membrane that also contained Rab5a and beta-arrestin 1, followed by rapid recycling of the NK1R. Overexpression of Rab5a promoted NK1R translocation to perinuclear sorting endosomes, whereas the GTP binding-deficient mutant Rab5aS34N caused retention of the NK1R in superficial early endosomes. NK1R translocated from superficial early endosomes to recycling endosomes containing Rab4a and Rab11a, and Rab11aS25N inhibited NK1R recycling. Rapid NK1R recycling coincided with resensitization of SP-induced Ca2+ mobilization and with the return of surface SP binding sites. Resensitization was minimally affected by inhibition of vacuolar H(+)-ATPase and phosphatases but was markedly suppressed by disruption of Rab4a and Rab11a. Thus, whereas beta-arrestins mediate NK1R endocytosis, Rab5a regulates translocation between early and sorting endosomes, and Rab4a and Rab11a regulate trafficking through recycling endosomes. We have thus identified a new function of Rab5a as a control protein for directing concentration-dependent trafficking of the NK1R into different intracellular compartments and obtained evidence that Rab4a and Rab11a contribute to G-protein-coupled receptor recycling from early endosomes.     

卵叶娃儿藤中的抗癌活性生物碱

从卵叶娃儿藤 (Tylophoraovata (Lindl.)Hook .exSteud .)根中分离得到 4个菲骈吲哚里西丁类生物碱 ,分别为tylophoridicineA (1)、娃儿藤宁 (2 )、氧甲基娃儿藤定 (3)和娃儿藤定 (4 )。经波谱分析并结合化学方法鉴定 ,其结构分别为 :(13aR)_6_羟基_3,7_二甲氧基菲骈吲哚里西丁、(13aS ,14R)_14_羟基_3,6 ,7_三甲氧基_菲骈吲哚里西丁、(13aS ,14S)_14_羟基_3,6 ,7_三甲氧基_菲骈吲哚里西丁和 (13aS ,14S)_6 ,14_二羟基_3,7_二甲氧基_菲骈吲哚里西丁。化合物 1为新化合物 ,化合物 2 - 4为首次从该植物得到的化合物。经药理筛选 ,化合物 1、3和 4显示很强的抗癌活性。     

Lys-63-linked Ubiquitination by E3 Ubiquitin Ligase Nedd4-1 Facilitates Endosomal Sequestration of Internalized α-Synuclein

α-Synuclein (aS) is a major constituent of Lewy bodies, which are not only a pathological marker for Parkinson disease but also a trigger for neurodegeneration. Cumulative evidence suggests that aS spreads from cell to cell and thereby propagates neurodegeneration to neighboring cells. Recently, Nedd4-1 (neural precursor cell expressed developmentally down-regulated protein 4-1), an E3 ubiquitin ligase, was shown to catalyze the Lys-63-linked polyubiquitination of intracellular aS and thereby facilitate aS degradation by the endolysosomal pathway. Because Nedd4-1 exerts its activity in close proximity to the inner leaflet of the plasma membrane, we speculate that after the internalization of aS the membrane resident aS is preferentially ubiquitinated by Nedd4-1. To clarify the role of Nedd4-1 in aS internalization and endolysosomal sequestration, we generated aS mutants, including ΔPR1(1–119 and 129–140), ΔC(1–119), and ΔPR2(1–119 and 134–140), that lack the proline-rich sequence, a putative Nedd4-1 recognition site. We show that wild type aS, but not ΔPR1, ΔPR2, or ΔC aS, is modified by Nedd4-1 in vitro, acquiring a Lys-63-linked ubiquitin chain. Compared with the mutants lacking the proline-rich sequence, wild type-aS is preferentially internalized and translocated to endosomes. The overexpression of Nedd4-1 increased aS in endosomes, whereas RNAi-mediated silencing of Nedd4-1 decreased endosomal aS. Although aS freely passes through plasma membranes within minutes, a pulse-chase experiment revealed that the overexpression of Nedd4-1 markedly decreased the re-secretion of internalized aS. Together, these findings demonstrate that Nedd4-1-linked Lys-63 ubiquitination specifies the fate of extrinsic and de novo synthesized aS by facilitating their targeting to endosomes.     

Dynamin and Rab5a-dependent trafficking and signaling of the neurokinin 1 receptor

Understanding the molecular mechanisms of agonist-induced trafficking of G-protein-coupled receptors is important because of the essential role of trafficking in signal transduction. We examined the role of the GTPases dynamin 1 and Rab5a in substance P (SP)-induced trafficking and signaling of the neurokinin 1 receptor (NK1R), an important mediator of pain, depression, and inflammation, by studying transfected cells and enteric neurons that naturally express the NK1R. In unstimulated cells, the NK1R colocalized with dynamin at the plasma membrane, and Rab5a was detected in endosomes. SP induced translocation of the receptor into endosomes containing Rab5a immediately beneath the plasma membrane and then in a perinuclear location. Expression of the dominant negative mutants dynamin 1 K44E and Rab5aS34N inhibited endocytosis of SP by 45 and 32%, respectively. Dynamin K44E caused membrane retention of the NK1R, whereas Rab5aS34N also impeded the translocation of the receptor from superficially located to perinuclear endosomes. Both dynamin K44E and Rab5aS34N strongly inhibited resensitization of SP-induced Ca(2+) mobilization by 60 and 85%, respectively, but had no effect on NK1R desensitization. Dynamin K44E but not Rab5aS34N markedly reduced SP-induced phosphorylation of extracellular signal regulated kinases 1 and 2. Thus, dynamin mediates the formation of endosomes containing the NK1R, and Rab5a mediates both endosomal formation and their translocation from a superficial to a perinuclear location. Dynamin and Rab5a-dependent trafficking is essential for NK1R resensitization but is not necessary for desensitization of signaling. Dynamin-dependent but not Rab5a-dependent trafficking is required for coupling of the NK1R to the mitogen-activated protein kinase cascade. These processes may regulate the nociceptive, depressive, and proinflammatory effects of SP.     

顶空进样气相色谱-质谱联用法分析木棉花挥发性成分

为研究木棉Bombax ceiba 鲜花的挥发性成分,采用顶空固相微萃取-气相色谱-质谱联用法(HS-SPME-GC-MS)进行鉴定分析。通过GC-MS,采用面积归一法从木棉花中鉴定了56 个主要组分及其相对含量。结果表明,主要组分为模菲(13.74%)、(1R,3aS,5aS,8aR)-1,3a,4,5a 四甲基-1,2,3,3a,5a,6,7,8-八氢环戊二烯并[c]环戊二烯(10.95%)、2-亚甲基-4,8,8-三甲基-4-乙烯基-双环[5.2.0]壬烷(10.36%)等。其中萜烯类化合物占55.24%,烷类化合物占29.72%,还有少量的醛类、酮类和酯类化合物。     

Isoflavonoids from roots of Erythrina zeyheri

Five isoflavonoids, (+/-)-7,2',4'-trihydroxy-8,3'-di(gamma,gamma-dimethylallyl)isoflavanone, (3R)-7,4'-dihydroxy-2'-methoxy-6,8-di(gamma,gamma-dimethylallyl)isoflavanone, (3R)-7,2',4'-trihydroxy-6,8-di(gamma,gamma-dimethylallyl)isoflavan, 2',4'-dihydroxy-8-gamma,gamma-dimethylallyl-2",2"-dimethylpyrano-[5,6:6,7]isoflavan and (6aS, 11aS)-3,6a-dihydroxy-9-methoxy-4,10-di(gamma,gamma-dimethylallyl)pterocarpan, along with five known compounds, were isolated from the roots of Erythrina zeyheri. Their structures were established on the basis of spectroscopic evidence, and their antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) were estimated by determining minimum inhibitory concentrations.     

Synthesis and anthelmintic activity of 7-substituted 3,4a-dimethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-diones

The racemic 7-substituted 3,4a-dimethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-diones represent novel tricyclic compounds with strong in vivo efficacy against the parasitic nematode Haemonchus contortus Rudolphi in sheep. Here we report on the synthesis of tricyclic endo-2,3-dihydro[3,2-b]pyridine-type cycloadducts and describe the separation of the racemic 3,4a-dimethyl-7-ethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2]pyridine-6,8(7H)-dione into the enantiomers by HPLC. The absolute configuration of the most anthelmintically active (4aS,5aS,8aS,8bR)-enantiomer was determined by single crystal X-ray analysis using its stable (4aS,5aS,8aS,8bR)-enantiomer-CuCl2 (2:1)-complex.     

Synthesis and SAR of tetrahydropyrrolo[1,2-b][1,2,5]thiadiazol-2(3H)-one 1,1-dioxide analogues as highly potent selective androgen receptor modulators

Replacement of the 3-oxo group of 2-chloro-4-[(7R,7aS)-7-hydroxy-1,3-dioxotetrahydro-1H-pyrrolo[1,2c]imidazol-2(3H)-yl]-3-methylbenzonitrile resulted in a sulfamide series of selective androgen receptor modulator (SARM) agonists.     

Correlation of secondary structures of bradykinin B1 receptor antagonists with their activity

The secondary structure of a bradykinin B(1)receptor antagonist B-10324 (F5C-Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-CpG(5)- Ser(6)-DTic(7)-CpG(8)) was determined by NMR at 800MHz. The conformational data are compared with those obtained previously for two bradykinin B(1) receptor antagonists, namely B-9858 (Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-Igl(5)- Ser(6)-DIgl(7)-Oic(8)) and B-10148 (Lys-(1)-Lys(0)-Arg(1)- Pro(2)-Hyp(3)-Gly(4)- Igl(5)-Ser(6)-DF5F(7)- Oic(8)). The abnormal amino acids are: Hyp, trans-4- hydroxyproline; Tic, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; Oic, (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid; Igl, alpha(2- indanyl)glycine; F5F, 2,3,4,5,6-pentafluorophenylalanine; CpG, alpha- cyclopentylglycine. F5C, pentafluorocinnamoyl, is the N-terminal protecting group and is not involved in the peptide secondary structure. B-10324 contains an N-terminal Pro(2)- CpG(5) distorted type II beta-turn whereas the rest of the peptide is random. A salt bridge is not observed between the carboxylate group at the C-terminal end and the Arg(1) side chain, in contrast to that previously observed for B-9858 and B- 10148. The conformations are correlated with the measured B(1) receptor antagonist activities (J.-F. Larrivée, L. Gera, S. Houle, J. Bouthillier, D. R. Bachvarov, J. M. Stewart and F. Marc au, Br. J. Pharmacol. 131, 885-892 (2000)). The importance of the N-terminal beta-turn is highlighted.     

Synthesis of novel pyrrolo[3,4-d]pyrazole-dicarboxylic acids and evaluation of their interaction with glutamate receptors

Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.     

蚜虫性信息素

蚜虫属同翅目蚜总科,是重要的农作物害虫。蚜虫长年行孤雌生殖,在中、高纬度深秋时,产生性蚜,以卵越冬。雌性蚜分泌性信息素荆芥内酯(nepetalactone)和荆芥醇(nepetalactol)。该文综述了蚜虫性信息素的结构与组分、性腺的形态结构、性信息素释放及影响因素;性信息素对雌性母和天敌的引诱作用;性信息素在蚜虫种间隔离中的地位和作用以及蚜虫性信息素在蚜虫防治中的应用前景。     

Isolation and identification of alectrol as (+)-orobanchyl acetate, a germination stimulant for root parasitic plants

Alectrol, a germination stimulant for root parasitic plants, was purified from root exudates of red clover (Trifolium pratense L.) and identified as a strigolactone, (+)-orobanchyl acetate [(3aS,4S,8bS,E)-8,8-dimethyl-3-(((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy)methylene)-2-oxo-3,3a,4,5,6,7,8,8b-octahydro-2H-indeno[1,2-b]furan-4-yl acetate], by 1D and 2D NMR spectroscopy and ESI- and EI-MS spectrometry. Orobanchyl acetate afforded an [M-42](+) ion in EI-MS and thus had been recognized as an isomer of strigol. Orobanchyl acetate was detected in root exudates of soybean (Glycine max L.) and cowpea (Vigina unguiculata L.) along with orobanchol.