氯霉素之合成研究(五) DL-threo-1-对硝基苯-2-氨基-1,3-丙二醇的分拆

研究了应用酒石酸来分拆DL-threo-1-对-硝基苯-2-氨基-1,3-丙-二醇为旋光体的基本数据。首先制备了D-和L-threo-1-对硝基苯-2-氨基-1,3-丙二醇,它們底酸性酒石酸盐和正酒石酸鹽,测定了物理常數(表1)。D-和L-threo-1-对-硝基苯-2-氨基-1,3-丙二醇的混合熔点曲線提示了混旋化合物的存在(圖1)。事实上,DL-化合物和其各別旋光体在水中的溶解度也不同(圖2). 酸性酒石酸盐和正酒石酸鹽在甲醇中,以及前者在水中的溶解度曲線,均經分別测定(圖3—5)。据此,我們建議了通过酸性酒石酸鹽,以甲醇或水为溶剂来提取的,旋光体分拆方法。     

氯霉素之合成研究(五) DL-threo-1-对硝基苯-2-氨基-1,3-丙二醇的分拆

研究了应用酒石酸来分拆DL-threo-1-对-硝基苯-2-氨基-1,3-丙-二醇为旋光体的基本数据。首先制备了D-和L-threo-1-对硝基苯-2-氨基-1,3-丙二醇,它們底酸性酒石酸盐和正酒石酸鹽,测定了物理常數(表1)。D-和L-threo-1-对-硝基苯-2-氨基-1,3-丙二醇的混合熔点曲線提示了混旋化合物的存在(圖1)。事实上,DL-化合物和其各別旋光体在水中的溶解度也不同(圖2). 酸性酒石酸盐和正酒石酸鹽在甲醇中,以及前者在水中的溶解度曲線,均經分別测定(圖3—5)。据此,我們建議了通过酸性酒石酸鹽,以甲醇或水为溶剂来提取的,旋光体分拆方法。     

新型免疫抑制剂2-氨基-2-[2-(4-正辛基苯基)乙基]-1,3-丙二醇盐酸盐(FTY720)的合成

目的 合成新型免疫抑制剂2-氨基- 2-[2-(4-正辛基苯基)乙基]-1,3-丙二醇盐酸盐(FTY720)。方法 以氯化苄和溴代正庚烷为起始原料,经Wurtz偶联、氯乙酰化、缩合、羰基还原、酯基还原、去乙酰化和成盐反应得到目的化合物FTY720,总收率为22.5％。结果与结论 目标化合物的结构经 1H-NMR、13C-NMR和MS确证。中间体的1H-NMR谱和熔点与文献值相符。该合成路线成本低廉,步骤较短,操作简单。     

（3S-反式）-3-氨基-4-甲基-2-氧代-1-氮杂环丁烷磺酸的合成

目的:以L-苏氨酸为起始原料,合成(3S-反式)-3-氨基-4-甲基-2-氧代-1-氮杂环丁烷磺酸。方法:以L-苏氨酸为原料,经氨基保护,N-酰化,羟基保护,磺化,环合,脱保护6步反应,制得(3S-反式)-3-氨基-4-甲基-2-氧代-1-氮杂环丁基磺酸。结果:目标化合物经熔点测定,收率12.92%.结论:该法操作简洁,设备条件不苛刻,收率较佳。     

(R)-3-氯-1,2-丙二醇及镇咳药左羟丙哌嗪的合成

目的制备高光学纯度的（R）-3-氯-1，2-丙二醇，并以此为原料改进镇咳药左羟丙哌嗪的合成工艺。方法以自制手性Salen—CoⅢ催化剂水解外消旋环氧氯丙烷得高光学纯度的中间体（R）-3-氯-1，2-丙二醇，该中间体再与N-苯基哌嗪反应合成镇咳药左羟丙哌嗪。结果与结论以手性Salen-CoⅢ催化剂水解环氧氯丙烷得到的（R）-3-氯-1，2-丙二醇光学纯度为99％；以此为原料合成的左旋羟丙哌嗪光学纯度为99％以上，收率为56．3％。目标产物经核磁共振氢谱、质谱确证。     

1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶的合成

目的:合成盐酸尼非卡兰中间体1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶.方法:以二甲基脲和氰乙酸为原料经3步反应合成目标产物.结果:以氰乙酸计,总收率44.4%.目标产物的光谱数据与文献报道一致.结论:新的合成方法所用原料价廉易得,适合生产.     

氯霉素的研究Lg-threo-1-对硝基苯基-2-氨基-1,3-丙二醇的消旋化

Lg-threo-1-对硝基苯基-2-氨基-1,3-丙二醇是氯霉素生产中旋光体的分拆一步所得的异构体,将它转变为混旋体,用以制取合霉素或氯霉素,具有较大的经济意义。我们采用Alberti法,并做了一些改进,其化学过程如下:     

近年来国外合成药及其中间体工艺简讯

氯霉素的新合成法民德专利,83,161(C.A.,1973,78,71663) 本专利报道从反式对-硝基栓皮醇为原料,与溴素在水中反应,可得1-对-硝基苯-2-溴代-1,3-丙二醇。然后在0℃时与氢氧化钾的甲醇溶液反应而得反式1-对-硝基苯-1,2-环氧-3-丙醇。将上述环氧物以氨水处理,并在甲醇中以酒石酸分拆,可得D(-)1-对-硝基苯-2-氨基-1,3-丙二醇,再经二氯乙酰化即得氯霉素,反应可用下式表示:     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

(3aR,6aS)-1,3-二苄基四氢-4H-呋喃并[3,4-d]咪唑-2,4(1H)-二酮的催化氧化工艺研究

目的研究1,3-二苄基四氢-4H-呋喃并[3,4-d]咪唑-2,4(1H)-二酮的转化利用及合成工艺。方法以1,3-二苄基四氢-4H-呋喃并[3,4-d]咪唑-2,4(1H)-二酮为原料,经醇解、TEMPO催化氧化和水解制得顺-1,3-二苄基-2-氧代咪唑-4,5-二羧酸。结果与结论目标产物结构经~1H-NMR和ESI-MS谱确证,总收率为77%(以原料计)。改进后的制备工艺具有反应条件温和、操作简便、收率高、成本低、环境友好的特点,适合于工业化生产。     

Effects of denervation, 6-hydroxydopamine and reserpine on the cholinergic and adrenergic responses of the spleen of the cod Gadus morhua

The effects of denervation of pretreatment with reserpine or 6-hydroxydopamine on the contractile responses of the cod spleen have been studied. The contraction produced by tyramine is abolished by pretreatment with reserpine or 6-hydroxydopamine and by denervation. The response to tyramine is restored in resperine-treated strips after exposure to noradrenaline, but this is not the case in the denervated or 6-hydroxydopamine-treated strips. The response to noradrenaline is potentiated by 6-hydrodoxydopamine treatment or denervation, while neither acute (2 days) nor chronic (8 days) reserpine treatment have any detectable effect. The effects of 6-hdyroxydopamine and denervation are probably due to specific supersensitivity caused by the loss of the presynaptic uptake mechanisms on destruction of the nerve terminals, but contribution by a non-specific postsynaptic supersensitivity is not completed excluded. The effect of acetylcholine is also significantly potentiated by pretreatment with 6-hydroxydopamine or denervation, but not reserpine, while the dose-response curve for carbachol is not affected by the specific cholinesterase inhibitor BW 284 C51, denervation or 6-hydroxydopamine. The degree of potentiation of the acetylcholine curve caused by both denervation and 6-hydroxydopamine treatment is very similar to that produced by BW 284 C51. It is concluded therefore, that the cholinesterase is associated with nerve fibres which destroys by denervation and 6-hydroxypamine. Although the cold spleen receives both cholinergic and adrenergic sympathetic innervation all responses to nerve stimulation of the perfused spleen are abolished after 6-hydroxydopamine treatment. The possibility is suggested that the symphatetic fibres to the cold spleen represent a primitive of neuron, with both catecholamines and acetylcholine present within the same terminals.     

决明子中大黄素的提取、分离和纯化方法的研究

目的寻求获得高纯度大黄素的可行性。方法先用稀硫酸溶液将蒽醌苷水解成苷元，再用热氯仿将苷元提取出来，然后用PH8．0缓冲液将大黄酸从氯仿液中除去，再用0．2％NaOH反复萃取将大黄素从氯仿液中提取出来，用层析柱法将大黄素分离纯化，经用丙酮反复多次重结晶可得纯度较高的大黄素。结果本方法提纯得到的大黄素的纯度达到98．1％以上。结论该方法操作简单、实用性强、成本低、可以推广应用。     

The effect of age and thyroid hormones upon the ability of the chick heart to deaminate monoamines

The effect of age and thyroid hormones upon the ability of chick heart homogenates to metabolize monoamines has been investigated. 5-Hydroxytryptamine is entirely metabolized by a monoamine oxidase (MAO) with the characteristics of MAO-A, whereas some of the tyramine and all of the benzylamine are oxidatively deaminated by a clorgyline-resistant, but semicarbazide-sensitive enzyme, with a similar subcellular distribution to that of MAO. The remainder of the tyramine deamination is brought about by MAO-A and MAO-B. The specific activities of both clorgyline-sensitive and resistant enzymes are increased by the same proportion by increase in age or by treatment with (-)-thyroxine, and decreased by 2-thiouracil. The significance of these results is discussed.     

The effect of age and thyroid hormones upon the ability of the chick heart to deaminate monoamines.

The effect of age and thyroid hormones upon the ability of chick heart homogenates to metabolize monoamines has been investigated. 5-Hydroxytryptamine is entirely metabolized by a monoamine oxidase (MAO) with the characteristics of MAO-A, whereas some of the tyramine and all of the benzylamine are oxidatively deaminated by a clorgyline-resistant, but semicarbazide-sensitive enzyme, with a similar subcellular distribution to that of MAO. The remainder of the tyramine deamination is brought about by MAO-A and MAO-B. The specific activities of both clorgyline-sensitive and resistant enzymes are increased by the same proportion by increase in age or by treatment with (--)-thyroxine, and decreased by 2-thiouracil. The significance of these results is discussed.     

用CHITOSAN固定化青霉素酰化酶

本文报道以Chitosan为载体制备固定化青霉素酰化酶的研究结果。1.4％ Chitosan醋酸溶液先用12.5％戊二醛交联,洗涤,研磨,得颗粒。再用1.5％pH5.5和1.5％pH8.5多聚磷酸处理,得机械强度良好的载体。此载体先后经0.5％戊二醛和对甲苯磺酰氯双活化后,再与青霉素酰化酶偶联。所得固定化酶的活力达20.8u/g。固定化青霉素酰化酶的反应最适温度略高于游离酶,最适pH略低于游离酶;其Km值基本接近游离酶。固定化酶经反复使用,活力基本不变。     

Nonhuman primates in behavioral toxicology: issues of validity, ethics and public health

The small, but vital, niche of nonhuman primates in neurotoxicology is examined. Several models of sensory and cognitive function have been especially useful with primates. Their sensitivity to low doses is clear. The validity of data from these models is indicated by their high correlation with data from intoxicated and normal humans, by the degree to which they approximate job functions and other vital human performances, and by their ability to document specific changes in behavioral function which correlate well with morphological and biochemical effects. The use of primates for this research is justified by the absence of adequate alternatives using nonprimate species, in vitro tests or computer programs. A series of experiments on the effects of methylmercury is used to illustrate ethical and scientific issues concerning research with primates. Recent trends are illustrated by data with trimethyltin.     

On the mechanism underlying the oscillatory current in cardiac Purkinje fibers

The mechanism underlying the oscillatory current (Ios) was investigated in sheep cardiac Purkinje fibers with a voltage-clamp technique. The Ios is initiated not only by repolarizing but also by a depolarizing clamp, provided that the preparation is preloaded with calcium by means of a conditioning clamp and that the depolarizing test clamp initiates the slow inward current. The Ios initiated by a depolarizing test clamp is usually smaller and has a longer time to peak than that initiated by a repolarizing clamp to the same potential. Brief depolarizing clamps can be followed by an Ios in fibers preloaded with calcium. The amplitude of Ios diminishes as the interval from the conditioning clamp increases. No Ios is initiated by repolarizing or depolarizing clamps to potentials positive to approximately -30 to -40 mV even when [Na]0 is lowered. If a test clamp is applied at a peak of Ios to potentials less negative than approximately -30 mV, the current disappears. The membrane conductance during the Ios is lower. It is concluded that Ios is initiated indirectly by repolarization and is due to a calcium-triggered release of calcium which may initiate an electrogenic Na-Ca exchange.     

The reduction of dithiobis(2-nitrobenzoate) by rat liver mitochondria

5,5'-Dithiobis(2-nitrobenzoate) (DTNB) is reduced in mitochondrial suspensions to 5-mercapto-2-nitrobenzoate (MNB) by 3-hydroxybutyrate and isocitrate. Although most of the MNB produced is found in the suspension medium, there is also some within the particles. The amount of MNB found in these fraction varies with the DTNB concentration used and is much lower if mitochondrial glutathione (GSH) is depleted with 1-chloro-2,4-dinitrobenzene. If hydroxybutyrate is present, the reduction of DTNB is increased by ATP and oligomycin. The pellet contains only a little MNB and GSH but these are considerably elevated by antimycin and rotenone as well as by ATP and oligomycin. If isocitrate is present, the reduction of DTNB is greatly stimulated by valinomycin, triethyltin and, to a lesser extent, oligomycin. MNB in the pellet falls and GSH concentrations are unchanged. The results suggest that with hydroxybutyrate (an NAD reducing substrate), the rate of reduction of DTNB is limited by the rate of regeneration of GSH while with isocitrate (an NADP reducing substrate) it is limited by the rate of export of MNB from the matrix.     

ctxB和ureB抗原表位的融合表达及其免疫学活性

为研制新型有效的幽门螺杆菌疫苗，设计了一个由ctxB(去除信号肽部分)和ureB抗原表位融合的新型分子。PCR扩增霍乱弧菌的ctxB基因，插入到质粒pEl32a上，再将化学合成的ureB抗原表位序列(编码的氨基酸为CHHLDKSIKEDVQFAQSRI）连接到ctxB下游，融合基因命名为ctube。将含有融合基因的pET32a转化到大肠杆菌BL21(DE3)，诱导表达后SDS-PAGE测定融合蛋白ctube的分子质量，ELISA法检测ctube对神经节苷脂GM1的结合活性，Western blotting检测对兔抗幽门螺杆菌(Hp)多抗的结合活性。序列分析结果表明，ctube基因全长387bp，编码129个氨基酸，其中ctxB的密码子与GenBank上的序列同源性达到99％。转化后的大肠杆菌BL21（DE3)经IPTG诱导表达后，产生了一个分子质量为2．5万的蛋白，经肠激酶酶切后的产物为ctube。ELISA试验和West Blotting表明，ctube与神经节苷脂性GM1、兔抗Hp多抗均具有很好的结合活性，有希望成为一个具有抗幽门螺杆菌感染的新的活性分子。     

Mechanisms involved in the pressor response to noradrenaline injection into the cingulate cortex of unanesthetized rats

The cingulate cortex (CC) is involved in cardiovascular modulation. CC electrical or chemical stimulation may evoke either pressor or depressor responses, depending on the stimulated site and experimental conditions such as anesthesia. Noradrenaline (NA) is involved in cardiovascular regulation and it is present throughout the cortex. However, there is no report on the cardiovascular effects of intracortical injections of NA. We attempted to verify the effect of NA injection into the CC and to identify possible receptor and peripheral mechanisms involved. NA injection caused pressor responses accompanied by bradycardia, in unanesthetized rats. These responses were markedly reduced under urethane anesthesia. The pressor response was blocked by intracortical pretreatment with phenoxybenzamine or the selective alpha(1)-antagonist WB4101, and it was not affected by pretreatment with the selective alpha(2)-antagonist RX821002, suggesting that alpha(1)-adrenoceptors mediate the response. The pressor response was potentiated by pretreatment with the ganglion blocker mecamylamine and it was abolished by pretreatment with the vasopressin antagonist, dTyr(CH(2)) (5)(Me)AVP or by hypophysectomy. Circulating vasopressin levels were increased after NA injection into the CC. The present results indicate that the pressor response to local injection of NA within the CC is independent of sympathetic nerve activation and is mediated by vasopressin release.