4-(4-苯基哌嗪-1-基)-3-O-甲基-D-肌醇的制备及镇咳活性

右旋肌醇甲醚经缩酮制化得3-O-甲基-1，2：5，6-二-O-异亚丙基-D-肌醇，经甲磺酰化、水解、与4-苯基哌嗪缩合制得左羟丙哌嗪类似物4-（4-苯基哌嗪-1-基）-3-O-甲基-D-肌醇，总收率38％。镇咳药效实验表明，目标物对致咳小鼠的镇咳作用明显，但不及左羟丙哌嗪。     

L-(-)-肉碱的合成

以自制手性salen-Co^Ⅲ为催化剂，水解动力学拆分外消旋环氧氯丙烷，得到高光学纯度的（S）-（＋）-环氧氯丙烷，再经季胺化、氰化、水解及离子交换制得L-（-）-肉碱，总收率70％[以（S）-（＋）-环氧氯丙烷计]。     

水解动力学拆分外消旋环氧氯丙烷--手性单核Salen-Co(Ⅲ)络合物的制备

环氧化合物是一类非常重要的有机物[1],尤其是末端环氧化合物在有机合成中有重要用途,用来合成各种各样的有机物,更重要的是光活性的环氧化合物[2,3],如S-(+)-环氧氯丙烷,是制备手性药物,生物试剂,化学试剂的重要中间体,在光活性有机物的合成中有着广泛的应用.外消旋的末端环氧氯丙烷是价廉易得的,水解动力学拆分外消旋环氧氯丙烷是吸引人的,简单和经济,在拆分过程中水是唯一的试剂,不加任何溶剂.我们已经成功地合成了Salen-Co(Ⅲ) 络合物(Scheme 1),在水解动力学拆分外消旋环氧氯丙烷中,被证明它是一种有效的不对称催化剂.在它的催化下,外消旋环氧氯丙烷组分中S-(+)-型和R-(–)-型的环氧物与水的反应速度大小不相同,最理想的结果是50%的D-(–)-型被水解得到50%的D-(–)-3-氯-1,2-丙二醇,同时释放出50%的S-(+)-环氧氯丙烷,这两个手性产物都是合成手性药物的重要中间体,这种HKR以式(1)表示:     

环氧氯丙烷的动力学拆分

目前,手性化合物的合成已经成为有机化学的一个重要发展方向。高纯度的手性化合物,对于化学、生物学以及药学都具有重要意义,特别是在药学研究中,对映体药物可以拓宽用途,减少剂量和代谢负担,提高活性和专一性,减少与其他药物的相互作用,并降低由其对映体可能引起的副作用。随着消旋体药物逐渐被淘汰,消旋体的拆分和手性化合物的合成就显得更为重要了。(S) -环氧氯丙烷作为一种重要的手性原料和合成中间体,在有机化工和制药领域,发挥着日益重要的作用。外消旋环氧化合物的动力学拆分是获得光学活性环氧化合物的有效方法之一。本文采用笼状烯胺和钴的复合物作催化剂,对混旋环氧氯丙烷进行动力学拆分,得到右旋环氧氯丙烷,光学纯度达到99% ,可用于合成左卡尼汀。     

牛肝酯酶催化紫杉醇侧链手性合成的研究

采用牛肝酯酶拆分紫杉醇侧链合成中生成的对映异构体化合物的新方法。牛肝酯酶催化拆分顺-3-乙酰氧基-4-苯基氮杂环丁酮，得到(S)(-)-醇和标的产物(R)-( )乙酸酯。所得(R)( )-乙酸酯反应产率≥97%，光学纯度≥99．6％。结论：牛肝酯酶可以作为手性合成的催化剂。     

多糖聚合物手性固定相高效液相色谱法拆分二苯甲醇类手性化合物

目的：对6个氯取代的二苯甲醇类手性化合物建立HPLC分析方法。对拆分反应进行监测,并用于拆分产物光学纯度的分析测定。方法：在正相高效液相模式下,采用Chiralcel OD—H和Chiralcel OB-H两种纤维素类手性柱以及Chiralpak AD—H直链淀粉类手性柱,以正己烷-异丙醇或正己烷-异丙醇-三氟乙酸溶剂系统为流动相,流速：0．5ml·min^-1,检测波长：210nm。结果：采用上述方法,基线拆分了合成手性中枢性镇咳药左旋盐酸氯哌啶[（-）cloperastine hydrochloride]的主要原料4-氯二苯甲醇等6个氯取代的二苯甲醇类手性化合物,建立了快速的手性高效液相色谱法。结论：本方法简便准确,可对手性合成反应进行监测和中间体质量控制;同时．对4-氯二苯甲醇和3-氟二苯甲醇的高效液相手性分析方法进行了对比研究。     

8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮的合成新方法

以2-氰基一3一甲基吡啶为原料，通过自由基反应、Wittig-Homer反应、水解、还原、环化反应合成氯雷他定的重要中间体8-氯-10，11-二氢-4-氮杂-5H-二苯并[a，d]-5-环庚酮，总收率为20％。其结构经元素分析、核磁共振、质谱确证。     

N-甲基-N′-氨基哌嗪合成工艺改进

N-甲基-N′-氨基哌嗪是合成甲哌力复霉素的中间体,其纯度影响到甲哌力复霉素的质量。目前国内所采用的工艺路线尚存在一些缺点:以六水哌嗪为原料经甲基化、水解、亚硝化、还原的合成工艺,N-甲基-N′-氨基哌嗪含量一般仅60％,质量欠佳;若以二乙醇胺为原料则二乙醇胺及80％水合肼来源较紧张;后处理时二法均用大量氯仿提取分离,影响劳动保护。     

4-(4-氯苯基)-3-甲基-2,4-二氧代丁酸乙酯的合成

对氯苯丙酮经烯胺化得4-[（Z）-1-（4-氯苯基）丙烯基]吗啉，再与草酰氯单乙酯缩合得利莫那班合成中间体4-（4-氯苯基）-3-甲基-2-4-二氧代丁酸乙酯，纯度91％，粗收率66％。     

1-乙酰基-4-(4-羟基苯基)哌嗪的合成

目的对抗真菌药酮康唑的重要中间体1-乙酰基-4-(4-羟基苯基)哌嗪的合成工艺进行研究。方法以六水合哌嗪和对氯硝基苯为原料合成目标化合物,并对工艺进行探索。结果得到目标化合物,总产率优于现行路线。结论该路线有希望用于工业化生产。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.