3,4-二氢吡咯[1,2-a]吡嗪-1-酮衍生物的合成及抗炎镇痛作用

目的研究(2H)-2-环己基-3,4-二氢吡咯[1,2-a]吡嗪-1-酮衍生物抗炎镇痛作用的构效关系。方法以2-吡咯甲酸甲酯为原料,经取代、环合,制备(2H)-2-环己基-3,4-二氢吡咯[1,2-a]吡嗪-1-酮(3);通过Friedel-Crafts酰基化反应,制得其6-酰基衍生物4a~4j。用小鼠测试了所合成化合物的抗炎和镇痛活性。结果与结论合成了10个未见文献报道的新化合物4a~4j,其结构经MS1、H-NMR分析确证。抗炎镇痛试验表明,有些化合物具有明显的抗炎和/或镇痛作用,其中化合物4d的活性与对照药布洛芬相当。     

3-取代-1(3H)-异苯并呋喃酮光学异构体的合成及抗血小板活性初步研究

目的为开发高效、低毒的新型抗脑卒中药物,设计一系列3-取-代1(3H)-异苯并呋喃酮衍生物,研究这类化合物的抗血小板活性。方法以邻苯二甲酸酐为起始原料合成了一系列3-取代-1(3H)-异苯并呋喃酮6a-g以及7a-g,拆分了化合物6a-g。使用Born氏法体外实验评价了这类化合物的抗血小板活性。结果抗血小板活性强弱顺序为:l-异构体>dl消旋体>d-异构体;烷基苯酞的活性要强于相应的烯基苯酞。所合成的目标化合物活性均弱于正丁基苯酞(NBP,6c)及阿司匹林(Asp)。结论异苯并呋喃酮类化合物抗血小板活性可能与分子大小及构型有关,不同取代基作用强度总体趋势随取代基增大而减弱,体内生物大分子可能对该类化合物存在立体选择性。     

2，3-二氢喹啉-4（1H）-酮缩氨基脲类化合物的设计、合成及抗真菌活性研究

目的合成一系列二氯-2,3-二氢喹啉4（1H）-酮缩氨基脲类化合物并测定其体外抗真菌活性。方法以二氯苯胺和丙烯酸为起始原料,经加成、环合制得中间体5,7-二氯-2,3-二氢喹啉-4（1H）-酮和6,8-二氯-2,3-二氨喹啉-4（1H）-酮;中间体与各种胪-取代的氨基脲缩合得到目标化合物;采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性,实验选用9种临床上常见的致病真菌为测试菌株,以氟康唑为阳性对照药。结果与结论合成的24个化合物均未见文献报道,其结构经。H-NMR、Ms谱确证;活性测试结果表明,多个目标化合物对测试真菌表现出较好的体外抑菌活性。     

3,4-二氢喹啉-2(1H)-酮衍生物的设计合成及抗精神分裂活性研究

目的 设计合成3,4-二氢喹啉-2(1H)-酮类化合物,考察其对D2、5-HT2A、5-HT1A受体的亲和力,并对代表化合物进行体内抗精神分裂活性测试.方法 7-羟基-3,4-二氢喹啉-2(1H)-酮与二卤代烷进行O-烷基化反应,再与相应的哌啶衍生物反应得到目标产物(Ⅰ1～Ⅰ11);对目标化合物进行了D2、5-HT2A...     

7-羟基-3,4-二氢-2(1H)-喹啉酮的合成及两个副产物的分离确证

目的 改进7-羟基-3，4-二氢-2（1H）-喹啉酮的合成方法。方法 以间氨基苯甲醚为原料，经N-酰化和分子内傅-克烃化反应合成。结果 合成了目标化合物，两步反应的总收率为59％，并且分离出第二步反应的两个副产物，它们的结构经波谱确证。结论 改进的合成方法适用于工业化生产。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED50值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

5-芳基-1,2-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛作用

目的 研究5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物的抗炎镇痛作用构效关系，寻找高效低毒、具有抗炎镇痛活性的新型吡咯里嗪酮衍生物。方法 以吡咯里嗪酮为母体，设计并合成了5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定了该类化合物的抗炎及镇痛活性。结果 用两条路线合成了10个目标化合物，经1H-NMR和MS确证其结构。小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用。结论 化合物Ⅲ1及Ⅲ5的抗炎活性优于对照药布洛芬；化合物Ⅲ5的镇痛活性优于对照药布洛芬；其中化合物Ⅲ5的抗炎及镇痛活性均强于对照药布洛芬，值得进一步研究。     

N-取代-5-羟基-1H吲哚-3-羧酸酯类衍生物的合成

目的:以阿比朵尔为先导化合物,设计并合成一系列4-取代胺甲基-5-羟基-1-烃基-2-苯硫基甲基-1H吲哚-3-羧酸乙酯盐酸盐.方法:以4-氯代乙酰乙酸乙酯为起始原料通过硫代、胺化、Nenitzescu反应、Mannich反应、成盐反应共5步反应制得目标产物.由薄层色谱(TLC)确定每步反应终点.结果:目标化合物结构经红外光谱、核磁共振光谱及质谱确证.结论:通过该合成方法合成了9个未见报道的新化合物.     

1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物的合成及其抗惊厥活性

目的寻找具有抗惊厥活性的1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.方法以邻苯二甲酸酐为原料,先制备酞乙酸,再依次与氯化亚砜、胺反应合成9个(Z)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物;以氯乙酸为起始原料,依次与氯化亚砜、胺、三苯基膦反应制得季磷盐,再与邻苯二甲酸酐经Wittig反应又合成9个(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.所有目标化合物的结构均经IR和1H-NMR确证.采用最大电休克发作实验(MES)对目标化合物进行抗惊厥活性筛选.结果合成了18个未见文献报道的新化合物.5e、5h和5i的抗惊厥活性ED50值分别为155.6、184.6和170.4mg·kg-1.结论 E型异构体较Z型异构体具有较好的抗惊厥活性,其构效关系和药理作用机制值得进一步研究.     

Modulation of in vivo immunoglobulin production by endogenous histamine and H1R and H2R agonists and antagonists

The present study was designed to delineate the immunomodulatory role of histamine receptors (H1R and H2R) and their antibody generation in a rabbit model. Six groups containing 18 rabbits each received either vehicle (sterile distilled water, 1 ml/kg x b.i.d), histamine (100 μg/kg x b.i.d.), H1R agonist (HTMT, 10 μg/kg x b.i.d.), H2R agonist (amthamine, 10 μg/kg x b.i.d.), H1R antagonist (pheniramine, 10 mg/kg x b.i.d.) or H2R antagonist (ranitidine, 10 mg/kg x b.i.d.). All animals were subsequently immunized with an intravenous injection of sheep red blood cells (SRBC). Estimations of total serum immunoglobulins (Igs), immunoglobulin M (IgM) and immunoglobulin G (IgG) were performed by ELISA and hemagglutination assay (HA) at days 0 (pre-immunization), 7, 14, 21, 28 and 58 (post-immunization). Both the ELISA and the HA showed similar production of Igs, IgM and IgG but the results were found comparatively more significant by ELISA as opposed to HA. Results showed that histamine could influence a detectable antibody response to SRBC early (i.e., at day 7), which lasted until day 58. Immunomodulatory processes showed suppression of an Ig generation in the H1R-antagonist group with enhancement in the H2R-antagonist group. The H1R-agonist group showed an increased Ig production in comparison to the H2R-agonist group. The IgM production was inhibited in the H1R-antagonist group as compared to the H2R-antagonist group, and it was also suppressed in H1R-agonist group as compared to H2R-agonist group. IgG production was inhibited in the H1R-antagonist group as opposed to the H2R-antagonist group. In contrast, the H1R-agonist group increased IgG production as compared to the H2R-agonist group. All the results were found to be statistically significant (p < 0.05 or p < 0.01). In conclusion, histamine and its receptor (H1R and H2R) agonists enhance antibody production by triggering the histamine receptors (H1R and H2R), and both the H1R antagonist and the H2R antagonist positively or negatively regulate the antibody production. The findings of this study may have clinical significance.     

联合应用H_1和H_2受体阻滞剂的研究进展

组胺H1R阻滞剂主要用于超敏反应性疾病 ,而H2 R阻滞剂主要用于消化系统性疾病。但最近几年发现联合应用能扩大它们的用途 ,在超敏反应性疾病的治疗、减轻药物的副作用、抗肿瘤、哮喘的治疗等方面均有较好的效果     

Synthesis, molecular modelling and biological evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone derivatives as antitumor agents

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines.     

Effects of impromidine- and arpromidine-derived guanidines on recombinant human and guinea pig histamine H1 and H2 receptors

Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H2 receptor (gpH2R) than at the human H2R (hH2R) in the GTPase assay. Additionally, such guanidines are histamine H1 receptor (H1R) antagonists with preference for the human relative to the guinea pig receptor. The purpose of this study was to examine structure-activity relationships of guanidines at human and guinea pig H1R and H2R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H2R and antagonistic activity at H1R as assessed in the steady-state GTPase assay. Species selectivity of derivatives was similar as compared with the parent compounds. None of the structural modifications examined (different aromatic ring systems and different ring substituents) was superior in terms of H2R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H2R. Guanidines exhibited distinct structure-activity relationships for H1R antagonism in a radioligand competition binding assay and the GTPase assay and for H1R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH2R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H1R.     

大流行流感与甲型H1N1流感

目的对大流行流感和甲型H1N1进行综述。方法参考国内外近期的有关文献和WHO的相关报道,介绍了流感病毒的基本知识、大流行流感的定义和发展,以及甲型H1N1流感的特点和流行现状等。结果与结论大流行流感具有传播性强、危害大等特点,2009年的甲型H1N1流感为21世纪的第1次大流感,应加以重视。     

甲型H1N1流感疫苗不良事件监测及评估

目的:分析甲型H1N1流感疫苗的接种情况,及时总结接种的监测与评估,为开展甲型H1N1流感防控提供参考。方法:对国内外2009年接种甲型H1N1流感疫苗的不良反应监测报告进行分析。结果:甲型H1N1流感疫苗被认为与季节性流感疫苗总体安全性近似。结论:在甲型H1N1流感大流行的背景下,接种该疫苗利大于弊。     

重组人乙型肝炎病毒核糖核酸酶H基因工程菌发酵条件的初步研究

目的研究表达乙型肝炎病毒核糖核酸酶H1及H2 (HBV -RNaseH1及H2 )工程菌的发酵条件。方法采用摇瓶发酵,研究不同宿主菌表达HBV- RNaseH1及H2的效果,同时对培养基、诱导时期、诱导时间、初始pH值等发酵条件以及质粒稳定性进行研究。结果选用EcoliBL2 1为宿主菌,在LB培养基中培养至A60 0nm为0 .6时,诱导表达4 .5h ,HBV- RNaseH1及H2表达量最高达33.6 %和30 .8%。且重组质粒具有良好的分离稳定性和结构稳定性。结论此发酵条件可以较好地提高HBV- RNaseH1及H2的表达量,为发酵规模的扩大奠定基础     

2-乙酰氨基芴诱导γH2AX焦点的形成

目的探讨DNA损伤剂2-乙酰氨基芴(2-AAF)是否可诱导γH2AX焦点的形成及γH2AX作为检测DNA损伤的一个新的特异指标的可能性。方法用2-AAF处理中国仓鼠CHL细胞,应用免疫荧光方法检测γH2AX焦点的形成,并通过中性彗星实验验证DNA损伤的程度。结果0.1,1,5和20mg·L-1的2-AAF都可使细胞核内γH2AX焦点数量及有γH2AX焦点生成的细胞数量增加,但只有20mg·L-12-AAF处理的细胞才出现明显的彗尾增长及有彗尾的细胞数量增加。另外,磷脂酰肌醇3-激酶(PI3K)家族抑制物渥曼青霉素可抑制2-AAF诱导的γH2AX焦点形成。结论2-AAF可通过激活PI3K家族成员使H2AX磷酸化,进而诱导γH2AX焦点的形成。γH2AX检测DNA损伤的敏感性优于彗星实验,因此,γH2AX有可能成为衡量DNA损伤程度的良好指标。     

Arsenite downregulates H3K4 trimethylation and H3K9 dimethylation during transformation of human bronchial epithelial cells

Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic‐induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS‐2B) cells. After 16 weeks’ exposure, cells were transformed by 0.1, 0.5 and 1 μm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 μm arsenite at 12 weeks, and 0.5 and 1 μm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A. Global dimethylated H3K9 (H3K9me2) was also decreased after exposure to 0.5 μm arsenite for 4, 8, 12 and 16 weeks and 1.0 μm arsenite for 8 and 12 weeks, which was associated with an increase of HDM activities. Our findings indicated that arsenite decreased global H3K4me3 and H3K9me2 levels during cell transformation by modulating the enzymatic activities of histone methyltransferases and/or HDMs, and by upregulation of KDM5A protein levels for H3K4me3.     

Determination of isotope abundance for deuterium-labeled compounds by quantitative 1H NMR + 2H NMR

Deuterated reagents have been used in many research fields. Isotope abundance, as the feature parameter of deuterated reagents, the precise quantification, is of great importance. Based on quantitative nuclear magnetic resonance technology, a novel method that combines ¹H NMR + ²H NMR was systematically established to determine the isotopic abundance of deuterated reagents. The results showed that the isotopic abundance of partially labeled and fully labeled compounds calculated by this new method was even more accurate than that calculated by classical ¹H NMR and mass spectrometry (MS) methods. In brief, this new method is a robust strategy for the determination of isotope abundance in large-scale deuterated reagents.