1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-(N-异丙基-N-取代氨基)-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入异丙基及取代氨基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、^1H—NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了15个目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物（6c）,（6d）,（6e）,（6f）和（6g）对除薰烟曲霉菌外的7种菌株都表现出了较好的抑菌活性。结论：取代氨基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链为取代苄基活性较好,且取代苄基侧链越短,抑菌活性越好。     

1-(1 H-1, 2, 4-三唑-1-基)-2-(2, 4-二氟苯基)-3-[N-异丙基-N-(4-取代苄基)]-2-丙醇的合成及抗真菌活性

目的研究具有异丙基结构的氮唑类化合物的抗真菌活性。方法引入4位羧酸酯取代的苄基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、1H-NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果合成了14个未见文献报道的目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物(1)和(2)对除薰烟曲霉菌外的7种菌都表现出了较好的抑菌活性。结论 4位羧酸酯取代的苄基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链越短,抑菌活性越好。     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-[N-环丙基-N-(4-取代苄基)]-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入4位羧酸酯取代的苄基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、^1H-NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了15个未见文献报道的目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物（1）,（2）和（3）对除薰烟曲霉菌外的7种菌都表现出了较好的抑菌活性。结论：4位羧酸酯取代的苄基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链越短．抑菌活性越好.     

1-(1H-1,2,4-三唑-1-基)-2-叔丁基-3-[(4-取代苄基)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性的研究

目的研究具有叔丁基结构的三唑醇类化合物的抗真菌活性以及各种4-（取代苄基）哌嗪侧链的引入对该类化合物抗真菌活性的影响。方法设计合成了13个未见文献报道的目标化合物，所有化合物结构均经^1H-NMR谱确证，部分经过IR、MS确证；选择8种真菌为实验菌株，测定其体外抗真菌活性。结果所有化合物对8种真菌均有一定的抑制作用。其中，Ⅲ7的抑菌活性优于氟康唑。结论引入叔丁基和哌嗪侧链设计的目标化合物都具有抗真菌活性，侧链取代基的电性效应和立体化学特征的改变对该类化合物的抑菌活性有一定的影响。     

雌酚酮3-醚衍生物的合成与生理活性初探

目的：合成雌激素3－醚化合物以观察雌激素活性，方法：以雌酚酮为原料，在3位与碱性侧相连，合成4个化合物，其中2个未见文献报道，并进行亲子宫和抗子宫和抗子宫活性测定，结果：经初步生理活性测定其雌激素活性明显小于母体化合物，结论：雌激素3－接上碱性侧链上对生理活性有影响。     

7-[(1 S,4S )-3,3-二甲基-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基]-喹诺酮化合物的合成与抗菌作用

以（4R）－羟基－L脯氨酸为起始原料，经8步反应合成了[(1S,4S)-3，3－二甲基－2－氧杂－5－氮杂二环[2.2.1]庚烷，以此化合物作为喹诺酮类的7－位侧链，合成了3个衍生物，并测定了它们对10株革兰阳性菌和6株革兰阴性菌的MIC值。结果表明，它们的体外抗菌活性均低于对照药加替沙星和环丙沙星。     

4,4’-O-双(2-羟基-3-取代氨基)丙基-4-去甲表鬼臼毒素的合成及抗肿瘤活性

为探索鬼臼毒素C_4位侧链结构与活性的关系,合成了5个标题化合物。体外药理试验表明新化合物对L1210白血病细胞与KB细胞生长抑制作用普遍强于依托泊甙,提示含有羟基和氨基的侧链可能为出现活性所必需。     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-(N-环己基-N-取代氨基)-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入环己基侧链结构,合成一系列目标化合物,所有化合物结构均经Ms、1H—NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了11个未见文献报道的目标化合物,部分化合物对所选真菌均表现出了一定的抑菌活性。结论：引入环己基对抗真菌活性影响较大。     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-[(4-取代)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性

目的研究不同取代哌嗪侧链的引入对三唑醇类化合物抗真菌活性的影响.方法设计合成了13个三唑醇类新化合物;选择8种真菌为实验菌株,进行体外抑菌活性测试.结果目标化合物对8种真菌特别是深部真菌均有一定的抑制活性,其中有8个化合物对白色念珠菌的MIC80值小于或等于0.125μg/mL,是氟康唑活性的4倍以上,与酮康唑活性相当.结论脂水分配系数和立体化学因素的改变对该类化合物体外抑菌活性有较大影响.     

Lactivicin衍生物的化学结构与抗菌活性的研究

本文根据３０个Ｌａｃｔｉｖｉｃｉｎ衍生物体外抑菌活性测定结果，分析讨论了这类化合物的化学结构与抗菌活性的关系，研究结果表明，Ｌａｃｔｉｖｉｃｉｎ衍生物具有广谱抗菌活性；其抗菌强度和抗菌谐主要决于４－位酰胺侧链的结构，对４－位酰胺侧链的进一步改造，将可能筛选出高效，低毒的优良品种。     

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.

     

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.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Glycofection: The Ubiquitous Roles of Sugar Bound on Glycoplexes

Glycofection (transfection by using sugar-substituted polylysine) was assessed in order to provide an alternative to viral vectors for the transfer of genes into vascular smooth muscle cells. A rabbit vascular smooth muscle cell line (Rb-1 cells) was selectively transfected by using glycoplexes (glycosylated polylysine/pSV2LUC complexes) in the presence of 10 mu M of the fusogenic peptide GALA. A sugar-specific transfection was obtained when the glycofection was conducted for 1 h with glycoplexes containing either alpha Gal, alpha -Glc, alpha -GalNAc, beta -GlcNAc, or beta -GalNAc residues. The gene expression was high after transfection, with glycoplexes bearing alpha Gal, alpha -GalNAc, or beta -GalNAc residues that were weakly internalized, and low with glycoplexes carrying Lact or Rha residues that were well taken up by cells. These results suggest that 1) glycofection can be a good approach for a selective transfer of genes intovascular smooth muscle cells, 2) an efficient uptake of the glycoplexes is not the unique limiting step for an efficient transfection, and 3) the sugar-dependent trafficking of the glycoplexes inside the cells may account for the transfection efficiency.     

直肠癌下切缘病理组织学分析

目的探讨直肠癌逆向浸润与下切缘的安全距离的关系。方法对36例直肠癌Miles手术和Dixon手术后标本的肿瘤下缘1.0cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查,观察直肠癌逆向浸润或转移的距离。结果36例直肠癌标本距癌肿下缘1.0 cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查均为阴性,结论直肠癌远恻逆向浸润或转移未见超过1.0cm,因此认为保肛手术时切除肿瘤远侧肠管(包括系膜)2.0cm是安全的。