人甲状旁腺素活性片段前体物Pro-Pro-hPTH(1-34)的制备及活性研究

目的制备出具有生物活性的人甲状旁腺素活性片段类似物,并对其活性进行考察。方法采用基因工程方法:大肠杆菌BL 21为宿主菌,pET 28a为表达载体,天门冬酰胺酶Ⅱ切除信号肽的C末端片段为融合伙伴,在融合伙伴和目的肽结合处引入Asp Pro酸敏感位点及二肽酶Ⅳ识别的N端Pro Pro位点,之后经诱导表达,酸水解使融合伙伴和目的肽分离。结果成功构建了hPTH(1 34)的融合表达体系,它能高效表达含hPTH(1 34)的融合蛋白,经纯化,得到多肽纯品,经鉴定,该多肽的分子量、氨基酸组成均与设计的分子相符,工程菌中用于编码该多肽的DNA片段其测序结果也与原设计相符,是表达该多肽的正确模板。该多肽在Parsons雏鸡分析及卵巢摘除大鼠模型试验中均显示显著活性。结论用基因工程方法成功地制备出人甲状旁腺素活性片段类似物,该产物具有显著生物活性及潜在的药用价值。     

人甲状旁腺素(1-34)的合成与聚乙二醇化修饰

目的合成人甲状旁腺素(1 34) [hPTH(1-34) ]并进行聚乙二醇化修饰。方法应用固相多肽合成方法合成并经高效液相色谱纯化得hPTH(1-34) ,Cys-hPTH(1- 34)和hPTH(1-34)-Cys-NH2 。Cys hPTH(1-34)和hPTH(1-34)-Cys-NH2 在水溶液(pH 7～8)中分别与平均相对分子质量为5 0 0 0的单甲氧基马来酰亚胺基聚乙二醇(mPEG50 0 0 MAL)反应,经高效液相色谱纯化得Cys(mPEG50 0 0 MAL)- hPTH(1-34)和hPTH(1-34)-Cys(mPEG50 0 0- MAL) -NH2 。结果hPTH(1-34) ,Cys(mPEG50 0 0 MAL) hPTH(1 34)和hPTH(1 34) Cys(mPEG50 0 0 MAL) NH2 的质谱和氨基酸组成分析结果均与理论值一致。hPTH(1-34) -Cys(mPEG50 0 0-MAL) NH2 保持了较好的体外活性,Cys(mPEG50 0 0- MAL) hPTH(1-34)保持了较好的体内活性。结论采用一种简便的方法成功实现了对hPTH(1-34)的N端或C端的聚乙二醇化修饰     

人甲状旁腺激素(1-34)突变蛋白的设计与活性验证

通过对NCBI数据库中不同物种同源序列进行比对protein-protein BLAST,并利用计算机软件DiscoveryStudio3.1进行分子对接和分子动力学模拟,对天然人甲状旁腺激素(1 34)的3个氨基酸R25K26K27进行Q25E26L27置换,并对突变体的生物活性进行了评价。结果显示:突变后PTH(1 34)-(RKK-QEL)和突变前PTH(1 34)多肽主链叠合后均方根偏差RMSD值为2.509 3,说明两者主链结构构象差异不大;PTH(1 34)-(RKK-QEL)与受体蛋白PTH1R的相互作用能为599.253 kcal.mol 1,较天然PTH(1 34)的554.083 kcal.mol 1增强7.5%;氢键数目由32对增加至38对;PTH(1 34)-(RKK-QEL)能显著刺激UAMS-32P细胞RANKL基因的表达(P<0.01),并抑制OPG基因的表达(P<0.01);PTH(1 34)-(RKK-QEL)作用于UAMS-32P和小鼠原代股骨骨髓细胞共培养体系时,能显著刺激破骨细胞的形成(P<0.01),并且活性高于PTH(1 34)标准品。     

2(1H)-喹啉酮类化合物的药理活性及构效关系

列举若干具代表性的药物，从抗精神失常、抗血小板聚集、正性肌力、抗肿瘤、抗溃疡和抗过敏作用等几方面综述2(1H)-喹啉酮类化合物的药理活性及构效关系。     

人甲状旁腺素(1-34)对新生大鼠成骨细胞碱性磷酸酶活性影响

目的：研究外源性hPTH(1-34)对原代培养成骨细胞ALP活性影响。方法：新生大鼠头盖骨中取成骨细胞,改良Gomori氏钙钴法染色鉴定,磷酸苯二钠法测定ALP活性,RT-PCR检测ALP mRNA表达。结果：10^-8 mol.L^-1 hPTH(1-34)以48 h为一循环,在每一循环的前12 h作用于细胞时,可使成骨细胞ALP活性较对照组增加最明显,hPTH(1-34) 48 h作用组,与对照相比细胞ALP活性无显著差异。hPTH(1-34) 12 h作用组,成骨细胞ALP mRNA表达最高。结论：hPTH(1-34)刺激成骨细胞内ALP活性升高与给药方式及药物浓度有关,间歇性给药成骨细胞内ALP活性升高。     

定量结构-活性关系在混合体系毒性预测中的发展(英文)

目的:预测麻醉型化合物卤代苯混合体系的毒性。方法:采用发光细菌对卤代苯的单一体系和混合体系进行毒性试验;利用特定的公式计算了混合物的分配系数;建立了混合体系的定量构效关系。结果:(1)建立了单一化合物的正辛醇/水分配系数与毒性的关系。(2)建立了二元混合体系的分配系数与毒性之间的定量结构模型。(3)用二元混合体系的QSAR模型预测了其它不同组份和不同毒性比例的混合体系毒性。结论:QSAR能很好地预测麻醉型化合物卤代苯混合体系的毒性,并且有助于该类化合物的混合体系毒性作用的评价。     

N-取代苯基-2-(4-取代苯基)环丙烷-1-甲酸乙酯-1-酰胺的设计、合成及抗肿瘤活性

目的设计、合成N-取代苯基-2-(4-取代苯基)环丙烷-1-甲酸乙酯-1-酰胺类化合物,并进行抗肿瘤活性研究。方法采用微波反应,经缩合、环化、水解以及酰胺化等反应合成目标化合物。所合成化合物经1H NMR谱图和质谱进行确证,并对其进行体外抗肿瘤活性筛选。结果设计、合成了20个环丙烷酰胺类化合物。体外药理活性实验显示,所合成的目标化合物具有较好的抗肿瘤活性,其中5b对A549细胞的IC50值为6.8μM,具有进一步研究的价值。结论对氯苯基取代化合物比对三氟甲基苯基取代化合物有更好的抗肿瘤活性;酰胺芳香环吸电子基团化合物活性优于供电子基团化合物。     

多糖的结构分析与构效关系

对多糖的结构、结构改造、合成机理及控制、药理作用、构教关系等进行分析与探讨,有利于多糖类新药的研究与开发.     

注射用重组人甲状旁腺素(1-34)在健康人体的药代动力学

目的研究注射用重组人甲状旁腺素(1-34)[rhPTH(1-34)](激素)在中国健康人体内的药代动力学特征。方法30名健康受试者随机分为10,20,40μg3个剂量组,每组10人,用免疫放射测定法(IRMA)测定人血浆中甲状旁腺激素(PTH)浓度。结果药代动力学参数:tmax分别为(32.5±9.5),(24.0±9.7)和(35.0±13.5)min;Cmax分别为(0.14±0.04),(0.20±0.05)和(0.30±0.04)ng.mL-1;t1/2分别为(47.7±12.1),(50.1±16.4)和(53.6±14.4)min;AUC(0-240)分别为(9.79±1.46),(15.42±1.66)和(32.72±3.16)ng.min.mL-1。结论单次皮下注射重组人甲状旁腺素(1-34)在低、中、高3个剂量内,Cmax和AUC呈线性增长,与剂量呈正相关;体内代谢呈线性代谢特征,与国外报道基本一致。     

吡酮酸类抗菌药物的研究Ⅷ.1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其类似物的合成和构效关系

为探讨构效关系,合成了1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其喹啉、萘啶、吡啶[2,3-C]哒嗪环系类似物16个。测定了对大肠杆菌的MIC。用Hückel分子轨道理论(HMO)方法计算了四个母体环上电子密度。结果表明:环中氮的位置对药效团——3位羧基和4位羰基氧原子上电子密度的影响较大而影响其抗菌活性。喹啉、萘啶两环系的3位羧基和4位羰基氧原子上的电子密度较高,其体外抗菌活性较高;而噌啉及吡啶[2,3-C]哒嗪两环系的电子密度较低,其体外抗菌活性较低甚至消失。     

2-(1-Hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones: Synthesis and evaluation of cytotoxicity

A series of 2-(1-hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones (oximes) was synthesized and evaluated for cytotoxicity against L1210 cells and A549 cells. These oximes showed a greater cytotoxic activity compared to those of 2-(1-hydroxyalkyl)-1,4-dimethoxy-9,10-anthraquinones as the hydroxyalkyl bioisosteres. The enhanced cytotoxicity assumed to be due to the improved water solubility of the hydroxyimino group. Moreover, it was found that the cytotoxicity of the oximes decreased with elongation of alkyl groups at the side chain. All of the synthesized compounds showed higher cytotoxicity against L1210 cells than A549 cells.     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇的合成及抗真菌活性研究

１（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）３取代２丙醇的合成及抗真菌活性研究张大志周廷森吴义杰刘超美麻铭川冯向庭（第二军医大学药学院，上海２００４３３）氮唑类化合物是目前抗真菌药物研究最为活跃的领域之一。该类化合物可分...     

Selective agonist binding of (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and 2S-(2alpha,3beta,4beta)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) receptors: a molecular modeling study

Molecular models were constructed, using the published X-ray structure of rat glutamate receptor 2 (GluR2), for the ligand-binding domains of the human (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)- and kainate-selective ionotropic glutamate receptors (iGluRs): GluR1-7 and KA1-2. Based on the analysis of the known X-ray structures of GluR2 in complex with glutamate, kainate, and AMPA, we have constructed binding motifs (relative positioning of a ligand in the binding site and the physico-chemical interactions that take place) for selected agonist ligands and found explanations for ligand-binding selectivity to homomeric receptors among the different iGluRs. Even a single sequence difference can explain significant differences in ligand-binding affinities between two receptors. In total, there are seven residues surrounding the binding cavity that affect agonist selectivity: in GluR2, these residues are Pro478, Thr480, Leu650, Ser654, Thr686, Tyr702, and Met708. Each of these seven positions has been shown, or is predicted, to influence the presence of one or more water molecules that, when present, may form bridging hydrogen bonds between particular ligands and receptors. By using this knowledge it should be possible to design new selective agonist ligands with high affinity for any AMPA/kainate receptor.     

2- or 6-(1-azidoalkyl)-5,8-dimethoxy-1,4-naphthoquinone: Synthesis, evaluation of cytotoxic activity; Antitumor activity and inhibitory effect on DNA topoisomerase-I

6-(1-azidoalkyl)-DMNQ derivatives compared to 2-(1-azidoalkyl)-DMNQ isomers, exhibited higher cytotoxic activity against L1210 mouse leukemia cells and stronger inhibition of DNA topoisomerase-I (TOPO-I), suggesting involvement of steric hindrance. However, similar antitumor activity against mice bearing S-180 cell was shown by 2- and 6-(1-azidoalkyl)-DMNQ derivatives.     

酪氨酸蛋白磷酸酯酶1B抑制剂的构效关系

介绍了最近几年来关于酪氨酸蛋白磷酸酯酶1B作用的机制以及通过各种途径发现的结构新颖的小分子抑制剂的构效关系研究进展。酪氨酸蛋白磷酸酯酶1B在胰岛素依赖的信号传导途径中发挥着非常重要的作用,并作为一个潜在的治疗2型糖尿病和肥胖的作用靶点日益受到广泛的关注。在其晶体结构被报道后,强效和选择性好的抑制剂更成为研制开发新药的焦点。     

N-〔3-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-2-羟基-丙基〕-氨基乙酸及其衍生物的合成和抗真菌活性

设计合成了Ｎ〔３（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）２羟基丙基〕氨基乙酸及其９个衍生物，均为未见文献报道的新化合物，初步药理试验表明：部分化合物对浅部真菌有一定的活性，除卡氏枝孢霉菌外，对其它深部真菌活性较弱，其中化合物（５ｅ），（５ｈ）对某些真菌的体外活性较强，明显优于氟康唑，但稍弱于酮康唑     

Convulsant, anticonvulsant and anaesthetic barbiturates. 5-Ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid and related compounds.

Barbiturates derived by minor structural changes to the butenyl sidechain of the convulsant 5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid are almost devoid of convulsant activity, but all have anaesthetic and anticonvulsant effects. Anticonvulsant activity is also observed in the convulsant barbiturate. Increased lipophilic character does not increase anaesthetic potency, only speed of onset, and anticonvulsant activity is reduced in the more lipophilic compounds. The stereochemistry at the 3'-position of the sidechain is vitally important to convulsant activity, and also influences anticonvulsant potency.