著名结构化学家卢嘉锡

著名结构化学家卢嘉锡郭保章（首都师范大学化学系，北京１０００３７）卢嘉锡谈吐幽默而又闪耀着智慧的光芒，平等待人而丝毫不给人以尊者和长者的感觉，与人坦诚相处而又得体，又是一位十分重视感情的人。他的朋友很多，大家都亲切地称他为卢老。１师友情卢嘉锡说：“在...     

以药物分子结构修饰为主题设计习题发展学生核心素养

以青蒿素、水杨酸、阿司匹林等药物分子结构修饰的发展史为素材设计了3组习题，分析了习题对促进学生"宏观辨识与微观探析""创新意识""模型认知""科学态度与社会责任"等化学核心素养发展的价值，论述了与素养达成目标相对应的关键能力的具体表现。     

重大新药创制“十二五”计划分批启动

6月16日,卫生部以2011年第17号公告的形式,正式宣：布重大新药创制专项“十二五”计划任务分批启动实施。其中,新药专项“十二五”计划2012年新增课题申报指南已通过专项总体组专家研究并编制完成。据悉,该期专项将重点支持“候选新药研究”和“新药Ⅳ期临床研究”两类研究课题,新药类别包括化学药、中药和生物药,鼓励开展药物新剂型和新释药系统的创新研究。     

竹红菌素的结构修饰

竹红菌甲素(简称甲素,HA)是一种新发现的苝醌衍生物,可作光疗药物和光敏化剂。为了筛选出更好的光疗药物,我们逐步修饰了竹红菌素的结构。痂囊腔菌素1的2位和11位甲氧基可被三氯化铝选择性地脱去甲基,而6位和7位的甲氧基不变化,但反应后产物难于分离提     

基于结构的组合库设计策略在新药创制中的应用

合理设计一些容量小的、针对特定靶标的化合物库(称为集中库,focused library),是当前组合库设计中的热点。当靶标的三维结构可以通过X射线衍射或NMR等手段确定后,人们就能采用几种不同的策略来进行组合库的设计。本文讨论了在靶标结合位点的约束下,进行组合库设计的主要方法及程序,同时强调了它们的优点与不足。通过这些方法的成功应用实例,显示了它们在新药创制中的广泛应用前景。     

利用亲和选择筛选法从组合化学库中筛选新药

组合化学方法可以产生大量的新化合物供新药筛选，但传统的逐一筛选法不能满足如此数量庞大的化合物，因此，针对混合物进行筛选显得非常重要，亲和选择筛选法利用药物作用的靶蛋白与潜在药物之间的亲和活性，使目标化合物与大量无亲和活性的化合物分离，然后只对有亲和活性的化合物进行结构鉴定，从而快速地从大量混合物中找到目标化合物，本文着重讨论了亲和选择筛选的的几种形，相应技术和在组合化学库筛选中的应用，亲和选择筛选大体分为两种方式：一种是将靶蛋白固定在支持物上，有亲和活力的化合物被保留，大量非亲和化合物被洗掉，另一种是在溶液中靶蛋白与混合物库孵育，然后利用受体配基复合物与不结合的游离化合性质的判别进行区分，亲和选择筛选法也适合于化合物的种类和含量都未知的天然提取物的筛选。     

化学家怎样看中药复方研究

最近，对中药复方进行科学的研究备受重视。这是一个好现象。它所探索的是中医学使用多种天然药物的总体效果的精髓，也表现了从近一个世纪单一成分研究上升到一个新的高度。植物化学研究者和传统中医药学研究者过去在自己的领域中耕耘，几乎不相往来，也不想往来，现在通...     

中国有机合成化学家的攀登

简要回顾了建国５０年、特别是近２０年来中国有机合成化学家们在于然产物及其类似物的合成方面所取得的若干具代表性的成就。     

抗肿瘤新药磷酸氟达拉宾的合成

磷酸氟达拉宾（7,fludarabine phosphate）由德国Bedex Labs开发,1991年首先在美国上市,用于治疗其它疗法无效的慢性淋巴细胞性白血病。本品摄入后经去磷酸作用生成代谢物9-β-氟阿糖腺苷（F-Ara-A）,后者在细胞内经磷酸化变成具抗肿瘤活性的F-Ara-ATP。本品的抗肿瘤机制涉及参入肿瘤细胞DNA或RNA链,使链停止延伸,以达到抑制DNA或RNA合成的目的。     

德国化学家学会——从成立至今日

对欧洲大陆最大的化学学会———德国化学家学会的成立背景、历史渊源、发展变革以及若干化学期刊的演变进行介绍,并阐述了德国化学家学会在高等化学教育领域所做的贡献。     

Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, were developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45128 as an inverse agonist. These compounds were then evaluated in vitro for their binding affinity by radioligand binding, their functional activity by ³⁵S-GTPγS coupling, and their cAMP accumulation in cells expressing the human DOR. Both compounds demonstrated high binding affinity and selectivity at the DOR, and both displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45128). Together, these results demonstrate that we have successfully designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.     

CCK1受体的同源模拟和分子对接研究

采用同源建模法对CCK1受体的三维结构进行了模拟,并采用分子动力学方法对模型进行修正和优化,再采用与训练集激动剂和拮抗剂分子对接的方法分别得到激动状态和拮抗状态CCK1受体的三维结构模型。得到的模型使用DOCK对接软件对训练集中的分子进行对接,所得结果与其实际活性拟合度较好,说明我们建立的激动和拮抗状态下的CCK1受体的三维结构模型比较合理,可以作为化合物虚拟筛选的模型对新化合物进行虚拟筛选。     

靶向Toll样受体4的小分子调节剂

Toll样受体(Toll-like receptors,TLRs)是进化保守的天然免疫模式识别受体,能够识别外源的病原菌相关分子模式(Pathogen-associated molecular patterns,PAMPs)、内源的损害相关分子模式(Damage-associated molecular patterns,DAMPs)和异源物相关分子模式(Xenobiotic-associated molecular patterns),诱导炎症免疫反应。 其中,TLR4(Toll-like receptor 4)是目前研究最为广泛的Toll样受体之一,TLR4是脂多糖(lipopoiysaccharide,LPS)的主要受体,LPS激活的TLR4信号通路在炎症信号的传递中发挥着重要作用,而此信号转导需要通过LPS与TLR4及其附属蛋白髓样分化因子2(myeloid differentiation factor 2,MD-2)的相互作用来实现。 因此,TLR4/MD-2成为炎症反应和免疫调控最重要的研究热点。 本文综述靶向TLR4/MD-2的小分子激动剂和抑制剂的研究进展,以进一步理解TLR4小分子调节剂与其相互作用的复杂性,帮助靶向TLR4/MD-2的免疫调节剂药物发现。     

Synthesis of the Chiral Pair of a Novel Thromboxane Antagonist, 3‐[2‐(3‐Benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] Propionic Acid

Preparation of the enantiomeric pair of 3‐[2‐(3‐benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] propionic acid, a novel thromboxane antagonist is reported. They are synthesized from either enantiomers of known (1R,2R,3R,4S)‐3‐[2‐(3‐carboxy‐7‐oxabicyclo[2,2,1]hept‐2‐yl‐methyl)phenyl]‐propionic acid methyl ester via epimerization, modified Curtius' rearrangement and sulfonylamino formation. Other derivatives may be prepared similarly.     

Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist

Summary We report the rational design of novel neurotensin mimetics through use of the Multiple Template Approach. This approach is based on our notion that a flexible peptide can be replaced by a partially flexible molecule, identified through testing a comparatively small number of molecules possessing a different intrinsic availability of conformations of the native peptide. The Multiple Template Approach has culminated in the discovery of a pharmacologically unprecedented agent, which behaves as a neurotensin antagonist at low concentration and as a full neurotensin agonist at high concentration.     

神经毒品解毒和戒瘾的新疗法──血液灌流疗法

贩毒吸毒是当今世界最严重的社会公害之一，对社会安定和人们的身心健康构成极大威胁。至今，解毒和戒瘾还一直沿用传统医疗手段。本文介绍了毒品的药理学和成瘾机制以及有关解毒戒瘾的治疗方法，着重探讨了血液灌流疗法在治疗毒品滥用上的应用前景。     

Efficient Synthesis of Olmesartan Medoxomil,an Antihypertensive Drug

This document describes a simple and robust process for the synthesis of olmesartan medoxomil. This tailored process allows us to synthesize olmesartan medoxomil on a large scale with 50% overall yield. Also, our process has excellent control of the impurity profile in all the stages.     

SYNTHESIS AND APPLICATION OF SOME NEW 5-SULPHONYL-N-HETEROCYCLO-8-HYDROXYQUINOLINE DERIVATIVES AS POTENTIAL DRUGS

Abstract

Some new sulphonyl-N-heterocyclo-8-hydroxy quinolines have been synthesised by the reaction of 8-hydroxyquinoline-5-sulphonyl hydrazide with different active methylene compounds. The pyrazole, pyrazoline, pyrazolidine and pyridazine derivatives were reacted with some metal cations to give the corresponding chelates. All synthesized compounds have been screened in vitro for their biological activities.     

Synthesis of 2-and 5-(1,1-Dimethyl-1,2,5,6-tetrahydropyridinium-3-yl)oxadiazoline Iodides

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Synthesis of 2— and 5—（1,1—Dimethy1—,2,5,6—tetrahydropyridinium—3—yl）oxadiazoline Iodides

A series of 2- and 5-(1,1-Dimethy1-,2,5,6-tetrahydropyridinium-3-yl)oxadiazoline Iodides,which might be used as M1 muscarinic receptor agonists,was synthesized from nicotinaldehyde and nicotinhydrazine,respectively.Their structures were characterized by ^1H NMR,IR,MS spectra and elemental analysis.