二氢卟吩p6醚类光敏剂的合成及光动力抗癌活性研究

目的 基于前期研究表明二氢卟吩f的3-乙烯基成醚修饰具有更强的光敏抗肿瘤活性而设计合成二氢卟吩p₆醚类光敏剂（1）,研究其初步体外光动力抗癌活性。方法 以蚕沙叶绿素a粗提物酸水解产物脱镁叶绿酸a（5）经碱及空气氧化降解制得的紫红素-18（4）为先导物,通过碱水解和CH₂N₂甲基化制得二氢卟吩p₆三甲酯（2）,2与33% HBr加成后再和烷氧醇发生亲核取代反应生成目标化合物（1）,并评价其对黑色素瘤B16-F10细胞的光动力杀伤效应。结果 6个目标化合物1a-1f对黑色素瘤B16-F10细胞的体外光动力抗癌活性均优于同类阳性对照药他拉泊芬和维替泊芬,其结构经电喷雾质谱（ESI-MS）、氢谱（¹H NMR）、碳谱（¹³C NMR）及电喷雾高分辨质谱（ESI-HRMS）确证。结论 二氢卟吩p₆醚类光敏剂具有光动力抗癌活性强、治疗指数（暗毒/光毒比）高等优点,值得进一步开发研究。     

13-酰胺基取代苦参碱衍生物的合成及抗肿瘤活性研究

目的 合成13-酰胺基取代苦参碱衍生物及研究该类化合物的体外抗肿瘤活性。方法 以槐果碱为原料,通过迈克尔加成（Michael addition）,叠氮还原酰化反应,制得系列13-位酰胺取代的衍生物,所有化合物结构均经¹H NMR等谱确证;选取人肝癌细胞（BEL-7404）和小鼠黑色素瘤细胞（K111）对所合成的目标化合物进行体外抗肿瘤药理活性筛选。结果 设计合成了9个新化合物,大多数化合物对两株肿瘤细胞都具有较强的抑制活性。结论 化合物4b和4e对人肝癌细胞（BEL-7404）有较强的抑制活性。     

4-氯-2-氧代-1,2-二氢喹啉-3-甲醛的合成工艺研究

目的 对4-氯-2-氧代-1,2-二氢喹啉-3-甲醛的合成工艺进行研究。方法 以苯胺为原料通过酯的氨解、环合、胺亚甲基化、水解反应得到目标化合物。结果 合成了目标化合物,并利用MS和¹H-NMR确证了结构,此路线所得产品收率为62.1%。结论 此路线操作简单,成本低廉,设计合理,收率高,适合该化合物的工业化生产。     

4-（2’,3’-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯的合成

目的 设计并合成4-（2',3'-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯。方法 以2,3-二氯苯甲醛为起始原料经缩合、环合、水解反应制备得到目标化合物。结果 合成了目标化合物,并利用MS和¹H-NMR确证了结构;HPLC归一化法测得质量分数为98.3%。结论 4-（2',3'-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯的合成为丁酸氯维地平中杂质的研究提供了方便。     

双模抗肿瘤光敏剂二氢卟吩e6-偕氟尿嘧啶的合成和生物活性

目的 文献报道氟尿嘧啶（5-Fu）与光敏剂联用具有协同抗肿瘤作用，笔者设计合成二氢卟吩e₆（化合物3）与5-Fu经酰腙键偶联的pH响应性、光化疗双模抗肿瘤光敏剂（化合物1），研究其初步体外光动力抗癌活性及作用机制。方法 首先，5-Fu与五硫化二磷于吡啶中回流反应形成4-硫代-5-氟尿嘧啶，再和水合肼于甲醇中反应制得5-氟尿嘧啶-4-腙（化合物2）；然后，将脱镁叶绿素a（化合物4）酸碱降解产物3经EDC·HCl催化缩合形成二氢卟吩e₆-13¹,15²-酸酐中间体后，直接与2发生选择性酰化反应，制得目标化合物1，并考察其体外pH响应性5-Fu释放及对黑素瘤B16-F10和肝癌HepG2细胞的光动力抗癌活性和作用机制。结果 化合物1在微酸（pH 5.0）环境中能有效释放5-Fu，24 h累积释放率可达60.3%；其在光照下对黑素瘤B16-F10和肝癌HepG2细胞的半数抑制浓度（IC₅₀）分别为0.73 μmol/L和0.90 μmol/L，均显著优于先导物3和上市药物他拉泊芬（talaporfin），且能显著提升肿瘤细胞内活性氧（ROS）水平和诱导肿瘤细胞凋亡，并阻滞肿瘤细胞周期于S期。其结构经紫外、电喷雾质谱、氢谱和元素分析确证。结论 新型双模抗肿瘤光敏剂化合物1具有光动力抗癌活性强、治疗指数（暗毒/光毒比）高，且可在微酸（pH 5.0）环境响应性释放5-Fu等优点，从而实现“单分子”光化疗双重抗肿瘤作用，值得进一步开发研究。     

双氯芬酸l-薄荷酯的合成与结构鉴定

目的 合成双氯芬酸钠凝胶剂中的杂质——双氯芬酸l-薄荷酯(化合物3),作为凝胶剂有关物质控制的对照品。方法 双氯芬酸钠(化合物1)经稀盐酸酸化得双氯芬酸(化合物2);将化合物2以EDCI为脱水剂,DMAP为催化剂,与l-薄荷醇发生酯化反应制得化合物3。结果与结论 目标化合物3的结构经IR、¹H-NMR和HR-MS(ESI)谱确证,纯度为99.60%。     

维达列汀主要杂质的合成

目的 为了加强抗糖尿病药物维达列汀原料药的质量控制,合成了维达列汀的3个特定杂质。方法 维达列汀（1）经闭环反应制得杂质A;以杂质A为原料经水解反应制得杂质B;维达列汀（1）经水解反应、酯化反应和闭环反应制得杂质B和杂质C。结果 合成的3种杂质的结构经过¹H-NMR、¹³C-NMR和LC-MS确证,纯度经HPLC检测>97%。结论 合成的3种杂质可以作为维达列汀原料药质量控制的杂质对照品。     

甲磺酸加贝酯的合成工艺改进

目的 改进甲磺酸加贝酯的合成工艺。方法 以己内酰胺（2）为原料,经水解、缩合两步反应制得中间体6-胍基己酸盐酸盐（4）,4与对羟基苯甲酸乙酯缩合后再经成盐制得目标化合物。结果与结论 目标化合物的结构经元素分析、红外光谱、核磁共振氢谱和质谱确证,总收率为43.1%,含量大于等于99.2%（质量分数）。该方法原料易得、操作简便、收率稳定。     

阿哌沙班的合成工艺改进

目的 改进阿哌沙班的合成工艺。方法 以3-吗啡啉-1-（4-硝基苯基）-5，6-二氢吡啶-2（1H）-酮（2）为起始原料，经缩合，氨化和"一锅法"还原和环合反应，得到阿哌沙班（1）。结果 中间体和目标化合物的结构经¹H-NMR、¹³C-NMR、高分辨质谱确证，3步合成总收率为50.2%。结论 改进后的工艺适合工业化生产。     

正交实验设计优化光敏剂紫红素-18的合成工艺

目的优化光敏剂紫红素-18（1）的合成工艺。方法以脱镁叶绿酸a（2）为原料,经空气氧化及碱开环制得化合物1;选择影响其合成产率的反应时间（A）、氢氧化钾溶液浓度（B）、反应溶剂（C）和化合物2与氢氧化钾的质量投料比（D）为考察因素,每个因素各取三个水平,采用L9（34）正交试验法优化目标物1的最佳合成工艺。结果合成目标物1的最优反应条件为B1C2A2D2,反应工艺收率从34.4%提高到45.6%。结论新工艺提高了收率、缩短了反应时间、消除了毒性溶剂,适合工业化生产     

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.

---

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.