(E)-4-酰氧基苯基丙烯酸类衍生物的合成及抑癌活性

报道了18个(E)-4-酰氧基苯基丙烯酸类衍生物的设计与合成。其中17个化合物未见文献报道。所有目标物的化学结构经元素分析、红外光谱和核磁共振氢谱确证。初步体外抑癌试验结果表明,化合物3e、3f、3g、3h、3k、4h和4j在0.3μmol·L-1浓度下对小鼠艾氏腹水癌(EAC)呈现显著抑制作用。     

6-(4-酰基-1-哌嗪乙酰氨基)-3,4-二氢-2(1H)-喹啉酮类化合物的合成及正肌力活性初探

目的 :寻找具有正性肌力活性的化合物。方法 :根据文献报道的二氢喹啉酮类正性肌力药物的结构特点 ,设计、合成了其类似物。以苯胺为起始原料经多步合成 ,对所得化合物用离体豚鼠心脏与主动脉观察了心肌收缩力、扩血管作用及心率。结果 :合成了 1 0个 6 ( 4 酰基 1 哌嗪乙酰氨基 ) 3 ,4 二氢 2 ( 1H) 喹啉酮类化合物 ( 4a～ 4j) ,均为未见文献报道的化合物。结论 :初步药理试验表明 ,化合物 ( 4h)显示了正性肌力及扩血管活性。     

6-(4-酰基-1-哌嗪乙酰氨基)-3,4-二氢-2(1H)-喹啉酮类化合物的合成及正肌力活性初探

目的:寻找具有正性肌力活性的化合物。方法:根据文献报道的二氢喹啉酮类正性肌力药物的结构特点,设计、合成了其类似物。以苯胺为起始原料经多步合成,对所得化合物用离体豚鼠心脏与主动脉观察了心肌收缩力、扩血管作用及心率。结果:合成了1 0个6-( 4-酰基1-哌嗪乙酰氨基)-3 ,4-二氢-2( 1HH) 喹啉酮类化合物( 4a～4j) ,均为未见文献报道的化合物。结论:初步药理试验表明,化合物( 4h)显示了正性肌力及扩血管活性。     

2-(2-取代苯基)噻唑-4-(甲)乙酸类化合物的设计、合成及抗肿瘤活性

目的为了寻找有效的Pin1小分子抑制剂,以2-苯基咪唑-4-甲酸为先导化合物,设计并合成了18个2-(2-取代苯基)噻唑-4-(甲)乙酸类化合物8a-8r。方法以2-甲氧基苯甲酸为起始原料,经8步反应得到目标化合物;利用已建立的酶活性筛选平台测试了目标化合物浓度为10μmol·L~(-1)时对Pin1酶的抑制率;采用MTT法,考察了目标化合物对人前列腺癌PC-3细胞的生长抑制作用。结果与讨论合成了18个未见文献报道的化合物,其结构经~1H-NMR谱和MS谱确证;多数化合物具有Pin1抑制活性,其中化合物8 h的抑制率达到100%;化合物的整体细胞生长抑制作用较弱,化合物8 c和8 g对PC-3细胞具有中等生长抑制作用。     

（E）—4—酰氧基苯基丙烯酸类衍生和的的合成及抑癌活性

报道了18个(E)-4-酰氧基苯丙烯酸类衍生物的设计与合成,其中17个化合物未见文献报道.所有目标物的化学结构经,红外光谱和核磁共振氢谱确证,初步体外抑癌试验结果表明,化合物3e,3f,3g,3h,3k,4h和4j在0\3umol.L^-1浓度下对小鼠艾氏腹水癌(EAC)呈现显著抑制作用.     

6-(4-取代乙酰氨基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其对血小板聚集的抑制作用

目的 设计并合成6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物,以期发现作用更强的血小板聚集抑制剂。方法以乙酰苯胺为原料,经酰化反应、傅-克反应、水解反应及水合肼环合反应、氯化反应、烷基化反应等一系列反应合成目标化合物,并参考Bom方法进行体外药理实验。结果共合成6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物11个,均属首次报道,并通过元素分析、^1HNMR、IR确证结构。初步的体外药理实验表明：大部分目标化合物都不同程度地抑制了ADP诱导的新西兰大白兔血小板的聚集。结论11个目标化合物中化合物(8)抑制血小板聚集作用的活性最强,超过对照化合物CCI-17810,化合物(1)、(2)、(4)等也有较强的活性。     

N~1-(4-取代氨基-6-三氟甲基-2-嘧啶基)-N~3-(卤苯基)胍的合成及其抗丝虫作用

报道了N~1-[4＇-[3-(二烷胺基)甲基和3, 5-双[(二烷胺基)甲基]-4-羟基苯胺基]-6-三氟甲基-2-嘧啶基]-N~3-(4-卤苯基)胍的合成。合成了24个化合物,经药理初筛表明,该类型化合物对感染沙鼠的棉鼠丝虫微丝蚴或成虫有一定的杀灭作用。     

4-(4-烷氧基苄基/苯乙基)-2H-1,2,4-三唑-3(4H)-酮类化合物的合成及其抗惊厥活性

目的设计合成一系列4-(4-烷氧基苄基/苯乙基)-2H-1,2,4-三唑-3(4H)-酮类化合物,并评价其抗惊厥活性和神经毒性。方法以对羟基苄胺和对羟基苯乙胺为起始原料,通过氨基保护、羟基烷基化、氨基脱保护以及氨基成三唑酮环反应合成目标化合物。采用最大电惊厥实验(MES)评价化合物的抗惊厥活性,采用旋转棒法测定其神经毒性。结果与结论合成了26个未见文献报道的新化合物,其结构经IR、1H-NMR、13C-NMR和EI-MS谱确证。活性实验结果表明,所有化合物在不同剂量下都显示出抗惊厥活性。其中,4-[4-(3-氟苄氧基)苯乙基]-2H-1,2,4-三唑-3(4H)-酮(9f)的活性最强,其半数有效量ED50值为19.5 mg·kg-1,保护指数(PI)为5.1。该化合物的PI值高于阳性对照药丙戊酸钠,低于卡马西平。     

2-烯基-4(1H)-喹诺酮的合成及生物活性研究

采用两种方法合成了3个2-烯基-4(1H)-喹诺酮(I～II),其中化合物II是从吴茱萸中分离得到的新化合物,其余2个化合物尚未见文献报道。并对所合成的化合物及中间体进行了初步药理试验,表明有一定的扩张血管和抗菌作用。     

N~1-(4-取代氨基-6-甲基-2-嘧啶基)-N~3-(对氯苯基)胍类的合成及其抗丝虫作用

报道了 N~1-[4-[3-(二烷胺基)甲基-和3,5-双[(二烷胺基)甲基]-4-羟基苯基]氨基]-6-甲基-2-嘧啶基]-N~3-(4-氯苯基)胍的合成。所合成的10个化合物进行了药理初筛,其中8个对感染沙鼠的棉鼠丝虫微丝蚴或成虫显示一定的杀灭作用。     

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.     

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.     

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.