Further Isolation of Coumarin from Angelica pubescence Maxim f.biserata Shan et Yuan

从重齿毛当归中进一步分得９个香豆素类化合物，它们是ｃｏｌｕｍｂｉａｎｅｄｉａｎ（１），ｏｓｔｈｏｌ（２），ｂｅｒｇａｐｔｅｎ（３），ｉｓｏｉｍｐｅｒａｔｅｒｉｎ（４），ｍｅｒａｎｚｉｎｈｙｄｒａｔｅ（５），ｎｏｄａｋｅｎｅｔｉｎ（６），ｍａｒｍｅｓｉｎｉｎ（７），ｃｏｌｕｍｂｉａｎｉｎ（８）和ａｎｇｅｌｉｄｉｏｌ（９）．其中，５～８为首次从该植物中分得，９为一新的天然产物。     

闹羊花和八里麻(Rhododendron Molle Sieb.et Zucc.)的镇痛作用及毒性

1.闹羊花,八里麻的各种剂型均具有一定的镇痛效力,其中以八里麻粉的作用较大.2.叙述了闹羊花、八里麻各种剂型的LD₅₀或MLD.根据本实验八里麻的镇痛指数为28.9.本文写作中承中国科学院植物研究所南京中山植物园代为鉴定所试的闹羊花及八里麻,又中国药学会武汉分会代为购得八里麻,谨此志谢.又我组助理技术员罗道英同志协助操作.     

Metabolism of 6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline. II. Role of liver catechol O-methyltransferase and glutathione

1. On i.v. administration to rats of ¹⁴C-6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline (PV2) 23% dose of ¹⁴C was excreted in urine and 72% in faeces. The pattern of metabolites showed ten ¹⁴C-PV2 derivatives and unchanged PV2. Seven metabolites have been characterized by comparison with authentic compounds e.g. the ketone of PV2, the N-oxide PV2, the demethylated metabolites 6-hydroxy-PV2, 7-hydroxy-PV2 and 6,7-dihydroxy PV2, the benzyl ring-hydroxylated metabolites, 3′-hydroxy-PV2 and 6,7,3′-trihydroxy-PV2. Unchanged PV2 and its metabolites are excreted both free and conjugated.

2. Enzymic O-methylation of 6,7-dihydroxy-PV2 by liver catechol-O-methyl transferase (COMT) in vitro produced 6-hydroxy, 7-methoxy-PV2. After blockade of COMT by pyrogallol in vivo, the excretion of 6,7-dihydroxy-PV2 was increased and the excretion of 6-hydroxy, 7-methoxy-PV2 decreased.

3. Hydroxylation of the benzyl ring of PV2 and its metabolites indicates the formation of an intermediate epoxide followed by glutathione conjugation. After glutathione depletion in vivo by diethyl maleate (DEM) liver covalent binding of ¹⁴C-PV2 metabolites was increased and biliary excretion of benzyl ring-hydroxylated PV2 metabolites decreased. Replacement of glutathione depletion by a cysteine derivative restored liver covalent binding and the excretion of PV2 metabolites to levels similar to those observed in control rats, indicating that glutathione conjugation may be an important metabolic pathway for the detoxication of PV2 and its metabolites in vivo.     

A Novel 4′-O-Diglycoside of Decarboxyrosmarinic Acid from Blepharis ciliaris

Abstract

A novel natural phenolic 1 was isolated from the hydroalcoholic extract of the aerial parts of Blepharis ciliaris (L.) B.L. Burtt (Acanthaceae), in addition to apigenin 7-O-glucoside 2 and apigenin-7-O-(3″-acetyl-6″-E-p-coumaroyl glucoside) 3. The structure of 1 was established as 3′,4′-dihydroxy-β-phenyl ethyl caffeate-4′-β-O-D-galactopyranosyl-(1′″→4″)-α-O-L-rhamnopyranoside [= 9′-decarboxy rosmarinic acid-4′-O-(1→4)-galactosyl rhanmoside]. Structures were determined by conventional methods of analysis, as well as by different MS and NMR techniques.     

Antitumor Agents. 125. New 4β-Benzoylamino Derivatives of 4′-O-Demethyl-4-desoxypodophyllotoxin and 4β-Benzoyl Derivatives of 4′-O-Demethylpodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

A series of 4-benzoylamino (5-17) derivatives of 4-O-demethyl-4-desoxypodophyllotoxin and 4-benzoyl (18-20) derivatives of 4-O-demethyl podophyllotoxin have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 5-13 and 15-17 are more potent than etoposide in causing DNA breakage, while compounds 9, 10, 13, 14, 16, and 20 are more active than etoposide in their inhibition of the human DNA topoisomerase II. The order for the enzyme inhibitory activity of the derivatives of 4-O-demethyl-4-desoxypodophyllotoxin is 4-arylamino > 4-benzylamino > 4-benzoylamino.     

Stereoselective inhibition of calmodulin-dependent cAMP phosphodiesterase from bovine heart by (+)- and (−)-nimodipine

Summary The inhibitory effects of racemic (±)-nimodipine and of optically pure (+)- and (–)-nimodipine on the basal and calmodulin-dependent activity of a cAMP phosphodiesterase from bovine heart were investigated. The inhibition by (±)-nimodipine could not be overcome by an excess of calmodulin. However, increase of the cAMP concentration in the assay from 2 × 10^–4 mol/l to 2 × 10^–2 mol/l caused a shift of the IC₅₀ for the inhibition by (±)-nimodipine from 2.8 × 10^–6 mol/l to 6 × 10^–5 mol/l. Dixon-plot analysis revealed an inhibitory constant of K _i = 2.3 mol/l, Experiments with the two enantiomers showed that (+)-nimodipine is by about one order of magnitude more potent than (–)-nimodipine. This contrasts with the stereoselectivity of the Ca²⁺ channel inhibitory activity on isolated rings of the rabbit basilar artery where (–)-nimodipine is more effective than (+)-nimodipine in relaxing the smooth muscle contracted by K⁺-depolarisation. It is concluded that cAMP phosphodiesterase may be an intracellular target for nimodipine and its inhibition may contribute to the pharmacological activity of this 1,4-dihydropyridine. Send offprint requests to Ch. Schachtele at the above address     

Isolation and characterization of α-(1→6)-glucans from Cistanche deserticola

Three unique polysaccharides (1–3) have been obtained from the 0.5 M NaOH extract of the stem of Cistanche deserticola Y. C. Ma. The results of methylation analysis, partial acid hydrolysis, ¹³C, ¹H NMR, ¹H–¹H COSY, HMQC and HMBC spectroscopic analyses indicate that they are all composed of glucose, having a backbone of α-(1 → 6)-glucan, and have different molecular weights. Their structures differ from that of linear starch.     

Tricin 4′-O-(erythro-β-guaiacylglyceryl) ether and tricin 4′-O-(threo-β-guaiacylglyceryl) ether isolated from Njavara (Oryza sativa L. var. Njavara), induce apoptosis in multiple tumor cells by mitochondrial pathway

Njavara is an important medicinal rice variety of Kerala, India widely used in Ayurveda for the treatment of rheumatoid arthritis, paralysis, neurodegenerative diseases and in rejuvenation therapy. The study evaluated, for the first time, antitumor effects of the two rare flavonolignans, tricin 4′-O-(erythro-β-guaiacylglyceryl) ether (compound 1) and tricin 4′-O-(threo-β-guaiacylglyceryl) ether (compound 2), isolated from ‘Njavara’ black. Both the compounds induced apoptosis in three cancer cell lines colon adenocarcinoma cell line HCT 116, ovarian cancer cell line SKOV3 and breast cancer cell line MCF-7. Chromatin condensation in the three cancer cell lines by Hoechst staining showed >50 % of apoptosis by compounds 1 and 2 at concentration 40 and 30 μg/ml, respectively after 48 h. Further studies substantiated that both the compounds targeted cancer cells through mitochondrial membrane potential loss and subsequent chromatin condensation. Both compounds significantly increased the Annexin V binding thus confirming compounds 1 and 2 to be potential apoptotic agents.     

Synthesis and Pharmacological Properties of 1-Aryl-4-(3′4′,5′-trimethoxybenzoyl)piperazines

A series of 1-aryl-4-(3′,4′,5′-trimethoxybenzoyl)piperazines (IIa - IIg) having structures containing 3,4,5-trimethoxybenzoyl fragments were synthesized and characterized. Compounds IIa and IIc - IIg demonstrated weak anxiolytic properties and moderately decreased the spontaneous motor activity in rats. Compound IIb exhibited anxiolytic activity comparable with that of buspirone but, in contrast to this reference drug, increased the motor activity of test animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 12 – 14, May, 2005.     

Inhibition of α-glucosidase and hypoglycemic effect of stilbenes from the Amazonian plant Deguelia rufescens var. urucu (Ducke) A. M. G. Azevedo (Leguminosae)

The control of blood glucose levels is critical in the treatment of diabetes mellitus. α-Glucosidase inhibitors are of great importance in reducing hyperglycemia, and plants have provided many of these agents. The present study aimed at investigating the effect of two stilbenes, lonchocarpene and 3,5-dimethoxy-4'-O-prenyl-trans-stilbene (DPS), isolated from the Amazonian plant Deguelia rufescens var. urucu, on α-glucosidase activity and on mice postprandial hyperglycemia. Lonchocarpene and DPS inhibited α-glucosidase in vitro, with pIC(50) values of 5.68?±?0.12 and 5.73?±?0.08, respectively. In addition, when given orally, DPS produced a significant reduction of hyperglycemia induced by an oral tolerance test, while lonchocarpene did not. Data suggest that DPS may have a potential use as an antidiabetic drug.     

Isolation, structural features and antitumor activities of sixpolysaccharides from Angelica sinensis （Oliv.） diels in vitro

AIM The previous work has demonstrated that the polysaccharides of Angelica sinensis (Oliv.) Diels have significantly antitumor activity and indicated that the activity is strongly dependent on their structures. However, the relationships between the structure and the activities are still ambiguous. Thus, at present, more efforts are being expended in seeking to isolate the polysaccharides from Angelica sinensis(Oliv.) Diels, measure their structural features and antitumor activities, and elucidate structure - activity relationships of polysaccharides. METHODS The roots of Angelica sinensis ( Oliv. ) Diels were extracted With water, separated by Sephacryl S-400 and DEAE-sephadex A-25 columns and further purifled on Sephadex G-100 column.     

Synthesis of 2′,3′-dideoxyisoguanosine from guanosine

2,3'-Dideoxyisoguanosine was synthesized from guanosine via intermediate 6-[(4-methylphenyl)thio]-2-oxo-9-(2',3',5'-tri-O-acetyl-beta-D-ribofuran osyl)-2,3-dihydropurine (4). The 2-oxo, 6-amino and 5'-hydroxy triprotected isoguanosine derivative was utilized to reduce high polarity and promote poor solubility of intermediates. The protecting groups for oxo and 6-amino were easily removed in reduction of olefin in ribose without additional reaction steps. 2',3'-Vicinal diol in ribose sugar moiety was transformed to olefin with Bu3SnH by radical reaction via bisxanthate. Removing 5'-O-TBDMS protecting group gave final product, 2',3'-dideoxyisoguanosine (12) in a 10% overall yield.     

Synthesis, anti-inflammatory activity, and QSAR study of some Schiff bases derived from 5-mercapto-3-(4′-pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide

The purpose of this research is to synthesize better anti-inflammatory compounds derived from 5-mercapto-3-(4′-pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide (5). 2-Substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazine carbothioamide derivatives (6a–j)/(7a–e) are synthesized by the condensation of 5 with variously substituted aromatic aldehydes/1H-indole-2,3-diones, respectively, under conventional and microwave irradiation methods. The microwave method is found to be superior with higher chemical yields, tremendous reduction in time, and is environmentally benign as compared to conventional heating method. The chemical structures of the newly synthesized compounds (6/7) have been confirmed by IR, ¹H NMR, and ¹³C NMR spectra and have been evaluated for anti-inflammatory activity by carrageenan-induced acute paw edema method in rats.     

Anti-nociceptive and anti-inflammatory activities of (−)-α-bisabolol in rodents

(−)-α-Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation of essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (−)-α-Bisabolol has generated considerable economic interest, as it possesses a delicate floral odour and has been shown to have antiseptic and gastroprotective activities. In this study, (−)-α-bisabolol was tested in standardised rodent models by gavage administration at doses of 100 and 200 mg/kg in the models of inflammation and 25 and 50 mg/kg in the models of nociception. In the inflammatory models of paw oedema induced by carrageenan and dextran, the mice treated with (−)-α-bisabolol showed smaller oedemas compared to animals treated only with the vehicle. (−)-α-Bisabolol was capable of reducing paw oedemas induced by 5-HT but not oedemas induced by histamine. (−)-α-Bisabolol demonstrated anti-nociceptive activity in the models of visceral nociception induced by acetic acid and in the second phase of the nociception test induced by the intraplantar administration of formalin. (−)-α-Bisabolol did not have any effect in a thermal nociception model using a hot plate but was able to diminish mechanical inflammatory hypernociception evoked by carrageenan. These findings suggest that the anti-nociceptive action of (−)-α-bisabolol is not linked to a central mechanism but instead is related to the inflammatory process. (−)-α-Bisabolol was able to decrease leukocyte migration, protein extravasations and the amount of TNF-α to the peritoneal cavity in response to carrageenan. Additionally, (−)-α-bisabolol reduced neutrophil degranulation in response to phorbol-myristate-acetate. We demonstrate, for the first time, the peripheral anti-inflammatory and anti-nociceptive activities of (−)-α-bisabolol.     

Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans

Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH₃, CH₃, CH₂CH₃, CH=CH₂, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K₂CO₃ (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC₅₀) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC₅₀:0.4∼2.8 μg/ml).     

异黄酮衍生物的合成Ⅰ.7-甲氧基-3′-N,N-二烷胺甲基-4′-烃基异黄酮的合成

合成了异黄酮衍生物1458,1441和1461。它们的合成是由间-苯二酚与对-硝基苯乙腈经Hoesh反应,制得(Ⅱ)。化合物(Ⅱ)与原甲酸乙酯环化成7-羟基-4′-硝基异黄酮(Ⅳ)。化合物(Ⅳ)中的硝基还原成氨基,再经重氮化,水解生成化合物(Ⅷ)。化合物(Ⅷ)经Mannich反应,合成了1458、1441、1461。合成的异黄酮衍生物对小鼠所做耐氧试验表明,1461具有明显的小鼠耐缺氧作用。     

4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素的合成和抗肿瘤活性

对4’-去甲表鬼臼毒素的C₄位进行化学修饰,合成和筛选了10个4-烷硫基-4-脱氧-4’-去甲表鬼臼毒素衍生物以进一步研究C₄位不同的原子和取代基与活性之间的关系及寻找结构简单、活性更强的抗肿瘤新药。4’-去甲表鬼臼毒素与硫醇在三氟化硼·乙醚或三氟乙酸存在下生成相应的硫醚,也可用硫醇与4β-溴-4-脱氧-4’-去甲表鬼臼毒素反应生成相应的硫醚。在体外筛选中,化合物10和12抑制L1210白血病细胞的活性与依托泊甙相当或更强,化合物9,10,12和15抑制KB细胞的活性与依托泊甙相当或更强。