具有降压和降血脂活性的二氢吡啶衍生物的合成

To develop new drugs with the effects of lowering blood-fat and blood pressure, compounds 1～7 and 10 were synthesized by the reactions of 2-methyl-2-[4-(4-chlorobenzoyl)phenoxy]propionyl chloride with a hydroxyl group in 1,4dihydropyridines. Compounds 8 and 9 were obtained by the reactions of 2-methyl-2-[4-(4- chlorobenzoyl)phenoxy]propionyl chloride with salicylic aldehyde first, and then with β-aminocrotonates. All 1～10 are new compounds, and their structures were elucidated by means of ¹HNMR and MS. The effects of compounds 1～10 on lowering cholesterol, triglyceride and blood pressure were investigated, and some of which were found to have the effects of lowering triglyceride and blood pressure.     

New Constitutents from the Fresh Stems of Opuntia Dillenii

Aim:To study the chemical composition of Opuntia dillenii Haw.Methods:Many kinds of chromatography methods were used in the isolation procedure,while the structures of isolated compounds were determined on the aids of NMR and MS spectral analysis.Result:Three new compounds,together with 14 known compounds,were isolated form the 80% ethanolic extract of its stems.Conclusion:The three new compounds,opuntioside I(2),4-ethoxyl-6-hydroxymethyl.a-pyrone(3) and kaempferol 7-O-β-D-glucopyranosyl (1→4)-β-D-glucopyranoside(4),wene characterized.     

A cell-based,high-throughput homogeneous time- resolved fluorescence assay for the screening of potential K-opioid receptor agonists

Aim： The aim of this study was to identify K-opioid receptor （KOR） agonists from a library of 80 000 small-molecule compounds and provide the experimental basis for the development of new analgesic candidates. Methods： The cell-based, high-throughput screen for human KOR agonists was based on the LANCETM cAMP assay. Preliminary structure-activity relationship （SAR） analysis was applied according to the compounds＇ structures. An acetic acid twisting experiment was used to verify the pharmacodynamics. Results： In total, 31 compounds were identified as KOR agonists after preliminary and secondary screening. Of these compounds, five demonstrated significant KOR-stimulating activity that was comparable to U-50,488, a selective KOR agonist. The ECho values for I-7, I-8, 1-10, 11-5, and 11-8 were 13.34±1.65, 14.01±1.84, 9.57±0.19, 14.94±0.64, and 8.74±0.72 nmol/L, respectively. Based on SAR studies, the stimulating activity of compounds with 5-phenyl-7-（trifluoromethyl）-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyrimidine （group I） and 3,4-dimethoxy-N-（2-oxoethyl）-N-p-tolylbenzenesulfonamide （group II） parent structures were higher than the compound with a 5-hydroxy-2-methylbenzofuran-3-carboxylic acJd （group III） parent structure. PharmacodynarnJc experiments JndJcated that 20-40 μg/kg ip of compounds 1-10 and 11-8 significantly decreased the number of writhes induced by acetic acid; this finding is consistent with the SAR studies. Furthermore, the analgesic effects of compounds I-10 and II-8 were significantly antagonized in the presence of the selective KOR antagonist nor-BNI. Conclusion： These findings collectively indicate that compounds I-10 and II-8 exhibit significant analgesic activities, providing evidence, at least in part, for their clinical application as new analgesic drugs.     

Central pharmacological effect of Chinese Materia Medica Cynanchum Chinese R. Br

Aim： To study the Central pharmacological effect of the water - and chloroform - extract compounds from Cynanchum Chinese R. Br. Methods： The minimal neurotoxicity of the extract - compounds were measured by rotorod test. The Independent activity test and the hypnotic synergism test by under threshold hypnotic dosage of pentobarbital were employed to evaluate the central pharmacological action of the extract - compounds. All the extract - compounds were evaluated for anticonvulsant activity by maximal electroshock （MES） and subcutaneous metrazol （MET） induced seizure. Result： The extract - compounds significantly inhibited the spontaneous motor activity dose - dependently in mice after intraperitoneal administration. The two extract - compounds promoted the hypnotic effect by under threshold hypnotic doses of pentobarbital, and the ED50 values were 2.36 g/kg and 0. 75 g/kg, respectively. Meanwhile, the water - extract compounds exhibited significant protection after intraperitoneal （ip） administration in MET - induced seizures and the ED50 value was 2.34 g/kg; however, the chloroform - extract compounds did not produced protective effect in this seizure model. On the other hand, the chloroform - extract compounds exhibited significant protection in MES and the ED50 value was 1.34 g/kg; the water- extract compounds had no protective effect. Both extract -compounds showed no neurotoxicity as compared with phenytoin. Conclusion ： The extract compounds from Cynanehum Chinese R. Br show inhibition effect on CNS, and the water - and chloroform - extract compounds show different anticonvulsant activities in different seizure models in mice.     

Molecular modeling,quantum polarized ligand docking and structure-based 3D-QSAR analysis of the imidazole series as dual AT~ and ETA receptor antagonists

Aim： Both endothelin ETA receptor antagonists and angiotensin AT1 receptor antagonists lower blood pressure in hypertensive patients. A dual AT1 and ETA receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT1 and ETA receptor antagonists. Methods： Molecular modeling approach combining quantum-polarized ligand docking （QPLD）, MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT1 and ETA receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results： 3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship： substitution of methoxymethyl and cyclooctanone might increase the activity against AT~ receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ETA receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT~ receptor but significantly increased its activity against ETA receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ETA receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT1 and ETA receptor antagonists. Conclusion： This study may provide some insights into the development of novel potent dual ETA and AT1 receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT1R and ETA receptors.     

Discovery of potent β-secretase （bace-1） inhibitors by the synthesis of isophthalamide-containing hybrids

Aim： The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase （BACE-1） bearing hydroxyethylene （HE） framework. Methods： First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results： Thirteen new compounds （6-18） have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance （NMR） spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion： This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer＇s disease.     

Synthesis and analgesic and antiinflammatory properties of new benzodiazepine derivatives

Several new N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides have been synthesized and characterized with respect to acute toxicity (LD₅₀), analgesic and antiinflammatory properties (formalin-and carrageenan-induced foot edema models), and interaction with morphine-induced antinociception in mice. The new compounds were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. The LD₅₀ of the synthesized compounds exceeds 1000 mg/kg. Three compounds produced significant analgesic action in doses 100–150 μg/kg in the early (painful) phase of the formalin test and potentiated the morphine-induced antinociception in this test. The synthesized drugs neither showed antinociception in the second (inflammatory) phase of the formalin test nor decreased the carrageenan-induced foot edema growth. Thus, the synthesized compounds produce analgesic action but do not possess antiinflammatory properties. The analgesic activity is probably due to the interaction with μ-and δ-opioid receptors. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 21–23, December, 2005.     

Inhibitory effects of phytochemicals on metabolic capabilities of.CYP2D6＊1 and CYP2D6＊10 using cell-based models in vitro

Aim： Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6＊1 and CYP2D6＊10 in vitro. Methods： HepG2 cells were stably transfected with CYP2D6＊1 and CYP2D6＊10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry. Results： HepG2-CYP2D6＊1 and HepG2-CYP2D6＊10 cell lines were successfully constructed. Among the 63 phytochemicals screened 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, iuteolin, schizandrin A and puerarin, at 100 pmol/L inhibited CYP2D6＊1- and CYP2D6＊10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose-dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6＊1 and CYP2D6＊10. However, their K1 values for CYP2D6＊I and CYP2D6＊IO were very close, suggesting that genotype- dependent herb-drug inhibition was similar between the two variants. Conclusion： Six phytochemicals inhibit CYP2D6＊1 and CYP2D6＊lO-mediated catalytic activities in a dose-dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6.     

Effects of resveratrol,curcumin and their derivatives on the activation of microglia induced by LPS

Objective To determine the inhibitory effects of 21 resveratrol derivatives and 3 natural curcuminoids on lipopolysaccharide(LPS)-induced Nitric oxide(NO)and tumor necrosis factor-alpha(TNF-α)production in microglia and their structure-activity relationships.Methods Cell viability was evaluated by the MTT reduction assay.Accumulation of nitrite(NO2-)in culture supernatant fluids was measured by the Griess reaction.Sodium nitroprusside(SNP)(2.5 mM)solution was used to determine the scavenging activities of these compounds.The levels of TNF-α in the culture medium were measured by using an ELISA kit.Semi-quantitative RT-PCR analysis was used to determine the mRNA levels of inducible NOS(iNOS)and TNF-α.Results It was found,for the first time,that certain resveratrol derivatives that have 3,5-dimethoxyl groups in the A-ring,such as(E)-4-(3,5-dimethoxystyryl)phenol(pterostilbene,compound 2),or have substituted the B-ring of resveratrol with quinolyl,such as(E)-5-[2-(quinolin-4-yl)vinyl]benzene-1,3-diol(compound 18)and(E)-4-(3,5-dimethoxystyryl)quinoline(compound 19),strongly inhibited NO production.Compounds 2,18,and 19 reduced LPS-induced protein and mRNA expression of inducible NO synthase(iNOS),but did not display direct NO-scavenging activity up to 30 μM in sodium nitroprusside(SNP)solution.Moreover,compounds 2,18,and 19 could also significantly inhibit the production of TNF-α by LPS-activated microglia.Furthermore,we found the demethoxy derivatives of curcumin have more potent inhibition activity on NO and TNF-α releasing in activated-microglia.Conclusions In the present study we compared the activated-microglia inhibition effect of resvertrol,curcumin and their derivatives and provided a glance of the structure-activity relationships of these compounds,the information is beneficial to design new potent compounds which can provide better therapeutic implications for various neurodegenerative diseases.     

A Monoterpene Glycoside from Ehinacea purpurea

Aim To separate and identify chemical constituents of Ehinacea purpurea. Methods Five compounds were isolated from the plant using chromatography. Their structures were elucidated by spectroscopy. Results Five compounds were isolated and their structures were identified as 2, 6-dimethyl-7-octene-2, 3, 6-triol-2-O-β-D-gtucopyranoside (1), 7, 8-furocoumarin (2), 6-methoxy-7-hydroxycoumarin (3), caffeic acid (4), methyl catfeate (5), and ethyl catfeate(6). Conclusion All these compounds were obtained from the plant for the first time.     

A STUDY IN MICE OF BROMO AND CHLORO ACYLUREA ANALOGUES OF THE SEDATIVE-HYPNOTIC BROMUREIDES

1. A series of 1-(2-chloroacyl)ureas, related to the sedative-hypnotic drugs brom-valetone and carbromal, was synthesized and tested in mice to determine central depressant and acute toxic effects. Four 1-(2-bromoacyl)ureas and two 3-halo compounds were included for comparison. 2. Large variations in potency were seen between the compounds. Much of this can be ascribed to differences in lipophilicity. Among homologous 1-(2-chloroacyl)ureas, those with 6 acyl carbons had maximal potency. Among groups of structural isomers, the most potent were 2-halo, 3-alkyl substituted compounds. 3. The most potent compounds were also those with the largest ratios of hypnotic to lethal activity. 4. The variation in the onset and duration of action of these compounds enables a choice to be made for a compound with a particular set of characteristics.     

抗血吸虫药物硝唑酰化物及其类似物的合成

硝唑眯(Ⅰ)是六十年代发现的抗曼氏及埃及血吸虫药物。对日本血吸虫也有治疗作用,但毒副反应较大,应用受到限制。考虑到药物分子中氨基经酰化后毒性往往降低的一般规律,我们设计合成了一系列硝唑咪酰化物。     

吡喹酮类似物的合成

本文合成了吡喹酮的3-位、6-位甲基取代衍生物(Ⅱ),2-位酰基、4-位内酰胺基还原产物(Ⅲ),以及C环开环化合物Ⅳ。并将合成的21个化合物进行了抗日本血吸虫的小鼠筛选,结果表明:3-位或6-位有甲基取代的化合物具有抗日本血吸虫活性,而当3-,6-位同时引入甲基,则活性大大下降,2-位酰基换成烃基或4-位内酰胺基还原成胺基均失去活性;部分C环开环化合物仍有活性,但较弱。     

2-去氧-2,3-去氢-N-三氟乙酰基神经氨酸8,9-二硫酸酯衍生物的合成

目的：合成2-去氧-2,3-去氢-N-三氟乙酰基神经氨酸(Neu5FA2en) 8,9-二硫酸酯衍生物。从中筛选有唾液酸酶抑制活性化合物。方法：以氢氧化钡脱除2-去氧-2,3-去氢-N-乙酰基神经氨酸(Neu5Ac2en)的N-乙酰基后,以三氟乙酸乙酯为三氟乙酰化试剂;以三氧化硫三甲胺复合物为硫酸酯化剂,合成目标化合物。结果：得到Neu5FA2en衍生物7个,均为新化合物。 结论：初步生物活性试验表明,所得化合物均具有一定的酶抑制活性,其中（10）的酶抑制活性较强。Neu5FA2en分子中三氟乙酰氨基与硫酸酯基具有协同作用,可增强对酶的抑制活性。     

根治间日疟化合物:2,5-双取代苯氧基伯喹衍生物的合成

作者等按Mislow等法先合成6-甲氧基-8-硝基-N-甲基-1 H-喹啉-2-酮后,在喹啉环2位及5位分别引入氯和溴,然后在2、5两位代入相同的取代苯氧基,再经还原、缩合、氯解等反应,最后合成了一类新的2,5-双取代苯氧基伯喹衍生物。化合物1,13和19对子孢子感染的鼠疟P.yoelii有效。     

苯并咪唑类化合物的合成及辐射增敏作用

为了寻找低毒和有效的辐射增敏剂,合成了苯并咪唑类化合物2-硝基苯并咪唑-1-甲酸乙酯,2-羟基苯并咪唑-1-甲酸乙酯及1-取代2-(3’-吡啶基)-5(6)-硝基苯并咪唑类化合物,并对小鼠Ehrlich腹水癌细胞进行了辐射增敏实验,初步结果证明所试化合物有不同程度的辐射增敏效果。     

2-吲哚醛西佛碱化合物的合成及其抗癌活性研究

目的：合成一系列吲哚-2-位西佛碱衍生物,通过药理筛选寻找具有抗癌活性的化合物。方法：通过亲核取代、还原、氧化、亲核加成等反应得到目的化合物。结果：设计合成了22个吲哚-2-位西佛碱新化合物,药理筛选结果显示2个化合物(5,14)对KB癌细胞株有抑制作用。结论：药理筛选结果表明,一些化合物显示了一定的抗癌活性,值得进一步研究。     

卟啉类衍生物的合成

卟啉类衍生物的合成已有七十余年的历史,其合成方法有以吡咯为原料的全合成,也有以易得的天然产物,如血红素等为原料进行半合成。自报道血卟啉衍生物(hematoporphyrin derivatives简称HpD)与激光结合用于诊治癌症以后,有关卟啉类的化学和临床研究,也迅速开展起来。1982年报道了单乙酰血卟啉、双乙酰血卟啉和乙酰氧乙基乙烯次卟啉在动物体内有对肿瘤的光敏活性,而纯血卟啉、原卟啉和羟乙基乙烯次卟啉却无效。为     

两头尖的化学成分研究

目的研究两头尖的化学成分。方法通过硅胶柱色谱,大孔树脂柱色谱及高压液相色谱等方法分离两头尖各部分提取物,根据理化性质和光谱分析鉴定化学结构。结果从两头尖根茎中分离得到9个化合物,分别鉴定为:27-hydroxyolean-12(13)-en-28-oic-acid-3-o-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (1),五加苷K(eleutheroside K, 2),oleanolic acid-3-O-α-L-rhamnopyranosyl-(1→2)-［β-D-glucopyranosyl-(1→4)］-α-L-arabinopyranoside (3),桦树脂醇(betulin, 4),桦树脂酸(betulic acid, 5),乙酰齐敦果酸(acetyloleamolic acid, 6),卫矛醇(evonymitol, 7),齐敦果酸(oleamolic acid, 8),薯蓣皂苷元(diosgenin, 9)。结论化合物1为新化合物,命名为raddeanoside 12。化合物3～7为首次自该植物中得到。