5-氟-(2-~(14)C)-尿嘧啶的合成

5-氟尿嘧啶(5-Fluorouracil)系抗肿瘤药物,据临床治疗证实:对直肠癌、结肠癌有显著疗效,对胰腺癌、胃癌和卵巢癌也有较好效果。本品曾由Stastug等用乙酸乙酯与~(14)-硫脲经缩合,环化反应制得,但放化得率较低(以~(14)C-硫脲计2.1％);Reerry等曾用(2-~(14)C)尿嘧啶直接氟代制得,得率虽较高,但实验条件要求较高。我们为了供应有关单位研究该药物对直肠癌肿瘤组织的摄取率及代谢过程,采用下列方法合成了5-氟-(2-~(14)C)-尿嘧啶。     

Inactivation of a class A and a class C β-lactamase by 6β-(hydroxymethyl)penicillanic acid sulfone

β-Lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) contribute significantly to the longevity of the β-lactam antibiotics used to treat serious infections. In the quest to design more potent compounds and to understand the mechanism of action of known inhibitors, 6β-(hydroxymethyl)penicillanic acid sulfone (6β-HM-sulfone) was tested against isolates expressing the class A TEM-1 β-lactamase and a clinically important variant of the AmpC cephalosporinase of Pseudomonas aeruginosa, PDC-3. The addition of the 6β-HM-sulfone inhibitor to ampicillin was highly effective. 6β-HM-sulfone inhibited TEM-1 with an IC(50) of 12 ± 2 nM and PDC-3 with an IC(50) of 180 ± 36 nM, and displayed lower partition ratios than commercial inhibitors, with partition ratios (k(cat)/k(inact)) equal to 174 for TEM-1 and 4 for PDC-3. Measured for 20 h, 6β-HM-sulfone demonstrated rapid, first-order inactivation kinetics with the extent of inactivation being related to the concentration of inhibitor for both TEM-1 and PDC-3. Using mass spectrometry to gain insight into the intermediates of inactivation of this inhibitor, 6β-HM-sulfone was found to form a major adduct of +247 ± 5 Da with TEM-1 and +245 ± 5 Da with PDC-3, suggesting that the covalently bound, hydrolytically stabilized acyl-enzyme has lost a molecule of water (HOH). Minor adducts of +88 ± 5 Da with TEM-1 and +85 ± 5 Da with PDC-3 revealed that fragmentation of the covalent adduct can result but appeared to occur slowly with both enzymes. 6β-HM-sulfone is an effective and versatile β-lactamase inhibitor of representative class A and C enzymes.     

(6S)或(7S)-甲氧基β-内酰胺类抗生素

(6S)或(7S)-甲氧基-β-内酰胺类抗生素具有良好的耐酶作用.目前已有多个品种上市,例如:头孢西丁、头孢美唑、拉氧头孢和替莫西林.其(6S)或(7S)-甲氧基造成的空间位阻是该类药物耐酶的关键所在.这种空间位阻作用使得其自身的结构对β-内酰胺酶稳定,从而解决或减少了大量使用β-内酰胺类抗生素而引起的细菌耐药性问题.化学合成这类药物可根据甲氧基取代C-6位氢原子的方法不同分为直接法和间接法.     

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.     

Kinetics and metabolism of (+)-, (−)- and (±)-bufuralol

Summary Single oral doses of (+)-, (–)- and (±)-bufuralol were administered to a healthy volunteer to compare the disposition and metabolism of the individual isomers and the racemate. Plasma levels and area under plasma curve (AUC) of the active isomer, (–)-bufuralol, were higher than those of the (+)-isomer; plasma clearance was correspondingly lower. Intermediate values were found for the racemate. The elimination half-life of (–)-bufuralol was shorter than that of (+)-bufuralol, but similar to the racemate. Both isomers were cleared almost entirely by metabolism. The main metabolic pathway for (–)-bufuralol was aromatic hydroxylation, whereas the principal route for (+)-bufuralol was conjugation. Phenol metabolites in the systemic circulation were present mainly as conjugates. Both isomers also underwent aliphatic hydroxylation. This pathway was more favoured by the (+)-isomer, although plasma levels and AUC of the principal product, 2-hydroxy-bufuralol, were almost identical for the two forms. Major differences in metabolic fate thus had relatively little effect on the disposition of pharmacologically active metabolites.     

Synthesis and Anti-inflammatory Activity of 2-(E)-(4-Hy-droxy-3-methoxybenzylidene)-5-(N-Substituted aminomethyl)Cyclopentanones

本文合成了１５种２（Ｅ）（３甲氧基４羟基苯亚甲基）环戊酮杂环胺Ｍａｎｎｉｃｈ碱盐酸盐和芳胺Ｍａｎｎｉｃｈ碱，并进行了初步的抗炎活性筛选。所有化合物结构均经波谱分析和元素分析证实。药理试验结果表明：部分化合物对二甲苯致小鼠耳肿胀有较显著的抑制作用；苯胺取代基的变化对芳胺Ｍａｎｎｉｃｈ碱的抗炎活性有显著的影响。     

Synthesis and antifungal activity of sulfides,sulfoxides, and sulfones based on (1S)-(-)-β-pinene

Attachment of 2-mercaptoethanol and thioglycolic acid methyl ester to the double bond of (1S)-(-)-β-pinene yielded pinane sulfides with the cis configuration. Oxidation of sulfides with m-chloroperbenzoic acid yielded the corresponding sulfoxides and sulfones. The resulting compounds were screened for antimycotic activity and the dynamics of changes in antifungal properties in sulfides-sulfoxide-sulfone series were studied.     

Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD)

Rationale

After decades of social stigma, hallucinogens have reappeared in the clinical literature demonstrating unique benefits in medicine. The precise behavioral pharmacology of these compounds remains unclear, however.

Objectives

Two commonly studied hallucinogens, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD), were investigated both in vivo and in vitro to determine the pharmacology of their behavioral effects in an animal model.

Method

Rabbits were administered DOI or LSD and observed for head bob behavior after chronic drug treatment or after pretreatment with antagonist ligands. The receptor binding characteristics of DOI and LSD were studied in vitro in frontocortical homogenates from naïve rabbits or ex vivo in animals receiving an acute drug injection.

Results

Both DOI- and LSD-elicited head bobs required serotonin_2A (5-HT_2A) and dopamine₁ (D₁) receptor activation. Serotonin_2B/2C receptors were not implicated in these behaviors. In vitro studies demonstrated that LSD and the 5-HT_2A/2C receptor antagonist, ritanserin, bound frontocortical 5-HT_2A receptors in a pseudo-irreversible manner. In contrast, DOI and the 5-HT_2A/2C receptor antagonist, ketanserin, bound reversibly. These binding properties were reflected in ex vivo binding studies. The two hallucinogens also differed in that LSD showed modest D₁ receptor binding affinity whereas DOI had negligible binding affinity at this receptor.

Conclusion

Although DOI and LSD differed in their receptor binding properties, activation of 5-HT_2A and D₁ receptors was a common mechanism for eliciting head bob behavior. These findings implicate these two receptors in the mechanism of action of hallucinogens.     

金催化甘露糖-b-(1→6)-甘露糖-b-(1→6)-葡萄糖三糖的合成

目的 利用金催化立体选择性构建b-甘露糖苷键的方法高效合成甘露糖-b-(1→6)-甘露糖-b-(1→6)-葡萄糖三糖。方法 以4,6-O-苄叉保护的甘露糖邻己炔基苯甲酸酯3为供体,在Au(I) 复合物和银盐催化下,与葡萄糖受体4反应,得到二糖产物5;二糖5在Bu₂BOTf/BH_3.THF条件下,将苄叉选择性还原开环至6-羟基,得到二糖受体6,进而再与糖基供体3反应,得到三糖2。 结果 分别以90%的产率、b/a = 14.2/1的选择性得到二糖5和88%的产率、b/a = 15.9/1的选择性得到三糖2。     

R-(—)-2-(6-甲氧基-2-萘基)─丙酸的两种消旋方法

Ｒ－（－）－２－（６－甲氧基－２－萘基）─丙酸的两种消旋方法牟振国（浙江省台州市椒江中医院，椒江３１７７００）在非甾体抗炎药萘普生（化学名：Ｓ（＋）－２－（６－甲氧基－２－萘基）－丙酸）的合成中，多数合成方法（１）均是先合成其消旋体，然后在适当的拆分...     

6-(4-(1-羧乙基)苯基)-5-氧代己酸的合成工艺改进研究

目的对6-(4-(1-羧乙基)苯基)-5-氧代己酸的合成工艺条件进行优化。方法以洛索洛芬为原料,通过取代、氧化、水解、再氧化反应得到目标化合物6-(4-(1-羧乙基)苯基)-5-氧代己酸。结果合成了目标化合物,经MS、1H-NMR确证了结构,质量分数为97%,本合成工艺的总收率为21.2%。结论合成了一种洛索洛芬的杂质,可作为洛索洛芬原料药质量控制的杂质对照品。     

神经肽ZNC(C)PR通过刺激C6细胞而对PC12起间接营养作用(英文)

目的:研究神经肽ZNC(C)PR通过C6细胞发挥的神经营养作用和机制。方法:以ZNC(C)PR处理C6细胞的条件培养液对PC12细胞生长的影响来观察该肽的间接营养作用,并用受体结合分析来确证该肽在此系统中作用的靶细胞类型。结果:ZNC(C)PR处理的C6细胞的条件培养液能够促进PC12细胞由嗜铬瘤细胞向交感神经元转化;放射性配体分析进一步指出在C6细胞上存在着该肽的特异性结合位点。结论:ZNC(C)PR能够通过位于C6细胞上的受体促进该细胞分泌某种营养性因子,通过这种因子促进PC12细胞的发育。     

5-乙酰-6-甲基-2(1H)-吡啶酮的合成

乙酰丙酮与丙烯腈经Michael加成,环合、脱氢可得到目标化合物5-乙酰-6-甲基-2-(1H)-吡啶酮。乙酰丙酮与丙炔酰胺在弱碱性条件下进行Michael加成,再环合也可得到目标产物。     

半边旗提取物6F抑制HL-6 0细胞蛋白激酶C活性(英文)

目的　探讨半边旗提取物 6F的细胞毒作用及诱导DNA片段化与蛋白激酶C(PKC)信号转导途径的关系 ,检测 6F对PKC活性的影响。方法　受试对象为HL 6 0细胞 ,超速离心法获得的胞液 (可溶部分 )及颗粒 (不可溶部分 ,包括细胞膜系统及胞核 )部分用作PKC活性测定。经 0 .4g·L- 1磷脂酰丝氨酸 ,0 .0 4g·L- 1甘油二油酸酯激动剂作用酶粗提物后 ,用液体闪烁计数仪计数 [γ 32 P]ATP参入外源底物的量以测定PKC活性。MTT法测定HL 6 0细胞的活力 ,二苯胺法测定 6F诱导DNA片段化程度。结果　在所测试的浓度范围内 (0 .5～ 312 μmol·L- 1) ,化合物 6F显著抑制胞液及颗粒部分PKC活性 ,最大抑制率达 88.6 % ,呈浓度依赖关系 (胞液部分r =0 .781,P <0 .0 5 ,颗粒部分r =0 .931,P <0 .0 1)。 6F诱导HL 6 0细胞DNA片段化及对细胞的毒性作用可被具有致癌作用的PKC激活剂肉豆蔻酸酯 (PMA ,浓度为 6 5nmol·L- 1)拮抗 ,抑制率分别是 30 %和 4 4% (P <0 .0 1)。PMA单独用使HL 6 0细胞线粒体将MTT还原为甲月赞的能力增强 14 % (P <0 .0 1) ,即增强细胞活力。结论化合物 6F是PKC的抑制剂。 6F对HL 6 0细胞DNA片段化的诱导作用及其细胞毒作用至少可部分归因于其对PKC活性的抑制作用     

固定化细胞制备6-氨基青霉烷酸(6-APA)新工艺

6-APA是生产半合成青霉素的关键中间体,由于半合成新青霉素已广泛应用于临床,而且在许多资本主义国家基本上已取代了青霉素,使6-APA的需要量日益增长。目前制备     

维生素C(抗坏血酸)缺乏症(坏血病)与补充维生素C

１维生素Ｃ的由来人类认识坏血病由来已久 ,早在１６０１年时人们就发现 ,饮食缺乏可引发疾病 ,但其治疗药物却姗姗来迟。至１９世纪初期 ,法兰西第三帝国统帅拿破仑率海军远征 ,士兵长年海上航行 ,吃不到新鲜的蔬菜和水果 ,每天仅以咸鱼和罐头果腹 ,结果绝大部分士兵患上了坏血病 ,牙龈和身体出血不止 ,全身乏力而失去战斗能力 ,以致全军覆没。从此 ,人们才开始重视抗坏血病药物的研制。天然的维生素Ｃ存在于新鲜的酸枣、桔子、柠檬等水果和柿子椒、西红柿、土豆、卷心菜等多叶的蔬菜中 ,参与体内的多种代谢过程 ,是防治坏血病的水溶性维生…     

6-甲基-4-(1H)-吡啶酮-3-羧酸的制备

目的制备 6 甲基 4 (1H) 吡啶酮 3 羧酸。方法以 4 羟基 6 甲基 2 吡喃酮、N ,N 二甲基甲酰胺二甲氧基缩醛为起始原料 ,经两步反应制得目标化合物。结果与结论经熔点测定及1H NMR、MS分析确证目标产物结构 ,总收率为 39 6 % ,高于文献收率     

(R)-( )-和(S)-(-)-β,β′-联萘酚的制备

手性试剂(R)-( )-和(S)-(—)-β,β′-联萘酚[( )-1和(—)-1]由于能制得高纯度的对映体,光学性质稳定,且具有很强的面不对称性,在不对称合成中易生成高比例 ee 值的产物。已成功地应用于不对称还     

5-氯(氟)-2,4-二氨基-6-(取代苄基氨基)喹唑啉衍生物的合成及其生物活性

根据氨基喹唑啉类化合物抑制叶酸代谢的机理及其构效关系,设计合成了以下三类喹唑啉化合物:Ⅰ,5-氯(氟)-2,4-二氨基-6-(取代苄基氨基)喹唑啉;Ⅱ,5-氯(氟)-2,4-二氨基-6-(N-甲酰-N-取代苄基氨基)-喹唑啉;Ⅲ,5-氯-2,4-二氨基-6-(N-亚硝基-N-取代苄基)氨基喹唑啉。所合成的18个化合物均为未知物,经元素和光谱分析确证其结构。化合物Ⅰ_(1～8)的合成采用5-氯(氟)-2,4, 6-三氨基喹唑啉(8,14)与取代苯甲醛缩合、还原而得,Ⅰ经甲酰化或亚硝化分别得到Ⅱ_(1～6)和Ⅲ_(1～4)。8的合成是将间氯苯胺与三氯乙醛、盐酸羟胺反应,得到的1-(α-肟基乙酰)3-氯苯胺(2)经环合后分除异构体得4-氯靛红(3a),3a经肟化、开环得到2-氨基-6-氯苄腈(5),5再与氰胺环合、硝化、还原即得8。14的合成尚未见报道。我们将5重氮化、氯化,再氟化制得2,6-二氟苄腈(10),10经氨化、环合得