具有抗癌活性的喜树碱类化合物的构效关系研究

目的 探寻喜树碱类似物的电子结构与抗癌活性的关系。方法 应用分子力学MM 法、量子化学从头算法和AMl法对18个喜树碱类似物进行几何优化，计算了化合物的电子结构，并应用逐步回归方法探寻化合物量子化学指数和抗癌活性的关系。结果 (1)喜树碱类似物的1og P与活性参数间呈抛物线关系；(2)分子的log P及20位碳原子电荷是影响化合物抗癌活性的重要因素；7位取代基的疏水参数1og P2对分子的log P影响很大；(3)得到较显著的QSAR方程：pIC50＝38．123 8．0907log P—0．81425(log P)^2—682．379QC20。结论 疏水性对喜树碱类似物的活性影响较大；D环及相连的羰基氧O23可能是与受体作用的活性中心；根据所得的QSAR及方程可以较准确地预测喜树碱类似物地活性。     

FRu（phen）2（3，8—2R—phen）-]^2＋（R=OH，H，F）电子结构与抗癌活性研究

用密度泛函(DFT)法，对配合物[Ru(phen)2(3，8-2R—phen)^2 (R=OH，H，F)进行了理论计算研究。探讨了配合物的电子结构与其抗癌活性的关系：主配体上3，8位上F原子的取代有利于配合物与DNA的作用，增加配合物的抗癌活性。计算结果能较好地预测配合物与DNA的作用强度、抗癌活性及指导具有较高抗癌活性配合物的合成。     

应用神经网络方法研究3—甲基芬太尼类似物的定量构—效关系

应用神经网络这种新型的信息处理系统研究定量松－效关系。方法：应用自编的逆传播神经网络算法，结合偏最小二乘法，研究了２５个３－甲基芬太尼类似物量子化学指数和镇痛活性之间的定量关系。结果：得到了良好的ＱＳＡＲ模型，３－甲基芬太尼类似物的量子化学指数即Ｎ１和Ｏ１６上净电荷，Ｃ１０－Ｃ９－Ｎ８－Ｃ４二面角，Ｃ７－ＰｈＡ中心的距离与镇痛活性之间具有很好的相关性，并根据计算，提出了芬太尼类似物与阿片受体的结合     

抗癌药物紫杉醇的发现,化学及构效关系

自从利用生物试验从植物提取物筛选新的抗癌化合物以来，已经发现了许多新的活性成分．但仅极少数化合物如长春碱、长春新碱、秋水仙碱、紫杉醇（Taxol）等，被最终研究开发成新的抗癌药物，而其中最令人们瞩目的则是近年来开发的紫杉醇．迄今发表。。有关紫杉醇及其类似物（taxoids）的研究资料颇为丰富，且有更加增多的趋势，已成为当今天然药物化学研究的“热点”．研究内容十分广泛，车要有植物化学（提取分离、结构测定）、分析、生理活性、化学修饰、合成、构效关系、生物技术、细胞生物学和分子生物学以及临床等。发表了许多综述、…     

紫杉醇及其衍生物基于逐步多元线性回归分析的QSAR研究

应用逐步多元线性回归方法，对紫杉醇及其衍生物的两个异构体系进行了构效关系研究，发现C13位侧链中的C3‘位取代基的摩尔折射与其活性密切相关，从而可以推断出C3‘位取代基的改变很可能是其生物活性变化的重要因素，这为设计与合成活性较高的紫杉醇类似物将提供有价值的参考信息。     

应用神经网络方法研究3-甲基芬太尼类似物的定量构-效关系(英文)

目的:应用神经网络这种新型的信息处理系统研究定量构-效关系.方法:应用自编的逆传播神经网络算法,结合偏最小二乘法,研究了25个3-甲基芬太尼类似物的量子化学指数和镇痛活性之间的定量关系.结果:得到了良好的QSAR模型,3-甲基芬太尼类似物的量子化学指数即N_1和O_(16)上净电荷、C_(10)-C_9-N_8-C_4二面角、C_7-PhA中心的距离与镇痛活性之间具有很好的相关性,并根据计算结果,提出了芬太尼类似物与阿片受体的结合模式.结论:神经网络方法研究结果优于单纯偏最小二乘法的结果,且能对化合物活性进行准确的预测.     

2—氯—5—（5，6—二氢—2—甲基—1，4—氧硫杂环己二烯—3—甲酰胺基）苯甲酸异丙酯类似物的合成和生物活性

2－氯－5－（5,6－二氢－2－甲基－1,4－氧硫杂环己二烯－3－甲酰胺基）苯甲酸异丙酯（UC84）具有显著的抗病毒活性。合成了该化合物并以其为先导物模型制备了十一个结构未经报道的类似物,活性筛选试验表明该化合物有明显的抗乙肝病毒（HBV）和单纯疱疹病毒（HSV）活性。     

14β—侧链紫杉醇类似物的合成

Sinenxan A(2)是一从红豆杉组织培养物中分离得到的具有紫杉醇母核A／B／C环骨架的化合物,以该化合物为起始原料,通过4,20－双键合成D－环,在14β－位引入侧链等合成了1,7,9,13－脱氧－14β－侧链紫杉醇类似物4和5,这两个化合物在体外活性实验中,对KB,A2780和HCT－8细胞株的细胞毒性比紫杉醇显著降低,10μmol.L^-1浓度下对微管蛋白聚合没有作用。     

杂环取代的二苯乙烯类化合物抗癌活性研究

目的：寻找新的抗癌化合物,方法：设计并用不同路线合成了１０个５－（或６－）杂环取代的－１,２－二苯基－１－烯类目的化合物,分别测定了它们抑制人鼻咽癌（）ＫＢ）和人宫颈癌（Ｈｅｌａ）细胞增殖的活性,并研究了其结构与抗癌活性之间的关系。结果：发现目的物对ＫＢ和Ｈｅｌａ细胞增殖均有一定的抑制作用,且抑制Ｈｅｌａ细胞的活性较抑制ＫＢ细胞强;定量构效关系（ＱＳＡＲ）研究结果认为取代基的诱导效应指数（Ⅰ）对活     

2-(E)-(4-甲基亚苄基)环戊酮曼尼希碱的合成及其抗炎活性研究

目的 合成2－（E）－（4－甲基亚苄基）环戊酮的曼尼希碱及其类似物并研究目标化合物的抗炎作用。方法 以N－环戊烯基吗啉、4－甲基苯甲醛及多种胺类为原料合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 共合成13个新化合物，经IR，^1H-NMR和MS确证其结构；部分化合物对二甲苯致小鼠耳肿胀具有较强的抑制作用。结论 2－（E）－（4－甲基亚苄基）环戊酮曼尼希碱类化合物具有较强的抗炎活性。     

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.

     

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.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.