纺锤体驱动蛋白抑制剂*

对纺锤体驱动蛋白(kinesin spindle protein,KSP)进行抑制代表着一种新颖的抗肿瘤机制,能避免直接破坏微管的药物所具有的不可避免的神经毒性。自第一个选择性的小分子KSP抑制剂monastrol报道以来,已有多种类型的KSP抑制剂有了文献报道。本文介绍了近年来KSP抑制剂的结构和功能,以及作为一个新颖的靶点在抗肿瘤药物研究中的作用;讨论了该类抑制剂的构效关系,并对该类抑制剂的研究前景进行了展望。     

环肽类组蛋白去乙酰化酶抑制剂

组蛋白去乙酰化酶抑制剂是一类以组蛋白去乙酰化酶为靶点的新型靶向抗肿瘤药物,在抗增殖、促凋亡、促分化、阻滞细胞生长周期、抗血管生成等方面有很好的作用。组蛋白去乙酰化酶抑制剂以其独特的抗肿瘤作用机理,在研发肿瘤治疗药物中占有重要地位。在组蛋白去乙酰化酶抑制剂分类中,环肽类抑制剂结构最为复杂,对多种类型的实体瘤及血液学癌细胞均具有良好的对抗作用。本文针对天然和化学合成的环肽类组蛋白去乙酰化酶抑制剂中金属结合区、表面识别区以及连接区的结构特点进行了综述,并描述了各类抑制剂对酶的抑制活性和抗肿瘤增殖活性。对抑制剂不同结构区的修饰、改造可以使抑制剂对不同肿瘤细胞具有高效性和特异性作用,通过构效关系研究寻找具有高效低毒、靶向性环肽类抑制剂的结构规律,可为研究开发抗肿瘤药物提供帮助。     

6-叠氮-6-脱氧凝聚多糖的选择性一步合成

由于含氨基或氨基衍生物的多糖对细胞表面及细胞之间的生理功能具有特殊的作用,在研究细胞之间有效作用的促进剂和抑制剂方面具有潜在的应用价值,因而叠氮化多糖作为制备氨基多糖及其衍生物的中间体受到人们的重视,含乙酰氨基的天然多糖（如Chitin）和氨基多糖（如Chitosan）,由于具有抗感染和医治创伤作用,广泛用于医疗领域,含氨基和硫酸酯的多糖肝素有很好的抗凝血作用和降血脂活性,已用于动脉硬化病的治疗,我们发现含乙酰氨基的硫酸化核聚糖具有很高的抗艾滋病毒活性,而且没有抗凝血的副作用。     

PAK4抑制剂的研究进展

p21活化激酶4（p21 activated kinase 4, PAK4）是丝氨酸/苏氨酸蛋白激酶,参与体内多条信号通路,影响肿瘤细胞的增殖、存活、侵袭转移及凋亡,对肿瘤的发生发展起着重要作用。近年来,PAK4成为抗肿瘤药物研发的新靶点,多种类型的PAK4抑制剂已被发现。本文根据PAK4抑制剂的作用机制不同,分别对ATP竞争性抑制剂、变构抑制剂和miRNAs抑制剂进行综述,主要从结构特征、生物活性及其合成方法等研究进展进行了总结和探讨。     

水溶性β-环糊精与华法林/阿魏酸包合物的制备及抗凝血性质测试和机理分析

采用研磨法和蒸馏法制备了阿魏酸(Ferulic acid,FA)和华法林(Warfarin,W)与β-环糊精(β-CD)的二元包合物,并采用红外光谱、紫外光谱、差热分析、扫描电镜和X粉末衍射法对其进行了表征,并在生理条件下研究了包合物的抗凝血性质及其与人血清白蛋白(Human serum albumin,HSA)的相互作用.结果表明,包合物的水溶性(包和物的溶解度约为5 g/L,华法林和阿魏酸为难溶物)和抗凝血指标都优于阿魏酸和华法林.与HSA作用的光谱结果表明,包合物可与HSA相互结合,增强了药物的血溶性,通过生成包合物避免了药物阿魏酸被氧化而失去原有的药效作用.说明华法林和阿魏酸经医药载体β-CD包合后水溶性增大,疗效增强,与HSA结合后可以达到药物通过血液输送的目的.     

抗凝血生物材料*

本文对抗凝血材料的研究进展进行了综述,着重介绍了血栓形成及凝血机理、提高生物材料表面抗凝血性能的改性材料和改性技术、抗凝血材料的表征等几方面的内容;分析了当前抗凝血材料研究中存在的问题,并对今后从分子水平上设计新型抗凝血材料进行了展望。     

三维全息原子场作用矢量(3D-HoVAIF)用于神经氨酸酶抑制剂的结构表征与设计及定量构效关系(QSAR)研究

对100个神经氨酸酶抑制剂抗禽流感药物结构并与其活性建立定量构效关系模型。采用本实验室提出的三维全息原子场作用矢量(3D-HoVAIF)对100个神经氨酸酶抑制剂进行结构表征,然后采用逐步回归对变量进行筛选后,运用偏最小二乘建立3D-HoVAIF描述子与神经氨酸酶抑制剂活性之间的QSAR模型。结果表明:复相关系数(R),交互校验的复相关系数(Q2)和模型的标准偏差(SD)分别为R2=0.805、Q2=0.657和SD=0.936,模型具有良好的稳定性和预测能力,并对文献中23个药物和设计的32个化合物进行了预测。表明三维全息原子场作用矢量能较好表征该类分子结构信息值得进一步推广应用。     

肿瘤血管生成抑制剂*

肿瘤血管生成的药物治疗是当前有关肿瘤的热点研究领域,目前已经有数种肿瘤血管生成抑制剂上市。肿瘤血管生成抑制剂能够抑制肿瘤的生长和转移,甚至使肿瘤消退。此类药物的研究开发可为肿瘤患者提供高效、低毒,并且抗瘤谱更广的药物。本文综述了近年来血管生成抑制剂的研究进展。首先介绍了间接血管生成抑制剂,此类药物中的血管内皮细胞生长因子受体信号通路的药物是目前最成功的一类血管生成抑制剂。其次介绍了直接血管生成抑制剂,使用这类药物更有可能避免间接抑制剂所引起的血管生成援救反应。然后在其他途径肿瘤血管生成抑制剂部分,本文详细介绍了作用机制尚不明确的沙利度胺及其衍生物。最后,本文分析讨论了这类药物的开发所遇到的一些问题,如抗血管生成治疗的新理论的挑战和耐药性等,并指出了未来发展方向。     

磷酸二酯酶2 (PDE2)结构及其选择性抑制剂的研究进展

磷酸二酯酶2 (PDE2)主要分布在大脑、心脏细胞中, 作为潜在的药物靶标, 通过水解细胞内第二信使cAMP和cGMP, 对维持cAMP和cGMP的水平起着重要的作用, 其选择性抑制剂有望在内皮渗透性和改善记忆力等方面发挥作用. 综述了PDE2的组织分布、生理功能、催化区域和调节区域晶体结构的特点以及选择性的抑制剂. 最后, 根据药物设计发展的趋势对未来PDE2抑制剂的设计进行了展望.     

抗肿瘤缺氧诱导因子-1的小分子抑制剂

肿瘤的缺氧微环境与其增殖、分化、血管生成、能量代谢、耐药性的发生以及患者预后状况密切相关。缺氧诱导因子1(Hypoxia-inducible factor 1, HIF-1)是细胞适应缺氧环境的重要转录因子和调控蛋白,通过调控下游靶基因如EPO、VEGF、GLUT等的表达,促进血管新生及有氧糖酵解以适应缺氧的环境,进而影响肿瘤细胞代谢、血管生成和肿瘤转移等。因此,开发以HIF-1为靶标的小分子抑制剂药物有望成为一种有效的肿瘤治疗方法。本文就HIF-1小分子抑制剂在肿瘤学研究中的进展进行综述,旨在为靶向HIF-1抗肿瘤药物的研发提供新思路。     

Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa

Factor Xa inhibitors are innovative anticoagulant agents that provide a better safety/efficacy profile compared to other anticoagulative drugs. A chemical feature-based modeling approach was applied to identify crucial pharmacophore patterns from 3D crystal structures of inhibitors bound to human factor Xa (Pdb entries 1fjs, 1kns, 1eqz) using the software LIGANDSCOUT and CATALYST. The complex structures were selected regarding the criteria of high inhibitory potency (i.e. all ligands show K(i) values against factor Xa in the subnanomolar range) and good resolution (i.e. at least 2.2 A) in order to generate selective and high quality pharmacophore models. The resulting chemical-feature based hypotheses were used for virtual screening of commercial molecular databases such as the WDI database. Furthermore, a ligand-based molecular modeling approach was performed to obtain common-feature hypotheses that represent the relevant chemical interactions between 10 bioactive factor Xa inhibitors and the protein, respectively. In a next step a virtual combinatorial library was designed in order to generate new compounds with similar chemical and spatial properties as known inhibitors. The software tool ILIB DIVERSE was used for this procedure in order to provide new scaffolds of this group of anticoagulants. Finally we present the combination of these two techniques, hence virtual screening was performed with selective pharmacophore models in a focused virtual combinatorial database. De novo derived molecular scaffolds that were able to adequately satisfy the pharmacophore criteria are revealed and are promising templates for candidates for further development.     

Oral,Direct Thrombin and Factor Xa Inhibitors: The Replacement for Warfarin,Leeches, and Pig Intestines?

To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep‐vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market.     

体积排阻色谱法测定低分子量肝素抗凝血因子Xa的活性

发展了一种基于体积排阻色谱测定低分子量肝素(LMWH)抗凝血活性的方法。利用肝素与抗凝血酶Ⅲ(ATⅢ)结合后可增强ATⅢ对凝血因子Xa(FXa)抑制作用的原理,通过测定加入LMWH后FXa水解其生色底物产生对硝基苯胺(pNA)这一反应的抑制程度确定LMWH的活性。首先将含有一定浓度LMWH的缓冲溶液与ATⅢ溶液混合,然后依次加入FXa和生色底物,分别孵育一段时间。底物被FXa水解,产生游离的pNA。体积排阻色谱可将小分子产物pNA与其他大分子分离开,因而可以在pNA的最大吸收波长下得到高灵敏度的测定,并且不再受其他成分的干扰。该方法重复性好,灵敏度高,极大地减少了样品的消耗量,降低了成本,并且还可进行各种复杂样品(如血浆)中LMWH抗FXa活性的监测。     

New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling,Synthesis, and Experimental Confirmation

In the modern world, complications caused by disorders in the blood coagulation system are found in almost all areas of medicine. Thus, the development of new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis is an urgent task. The blood coagulation factor XIIa is one of the most promising therapeutic targets for the development of anticoagulants based on its inhibitors. The initial stage of drug development is directly related to computational methods of searching for a lead compound. In this study, docking followed by quantum chemical calculations was used to search for noncovalent low-molecular-weight factor XIIa inhibitors in a focused library of druglike compounds. As a result of the study, four low-molecular-weight compounds were experimentally confirmed as factor XIIa inhibitors. Selectivity testing revealed that two of the identified factor XIIa inhibitors were selective over the coagulation factors Xa and XIa.     

Exploring the active site of human factor Xa protein by NMR screening of small molecule probes

A collection of small molecules (MW < 350 Da) was screened for binding to human factor Xa using saturation transfer difference NMR spectroscopy to detect binding. The NMR screening experiments identified four hits. Binding isotherms constructed from NMR linewidth data showed that the binding affinities of the hits were all in the 30-210 microM range. Competition binding experiments showed that three of the ligands were displaced by a known microM inhibitor of factor Xa. The success of the method for identifying new ligands and the relevance of this information to the design of new factor Xa inhibitors are discussed.     

基于天然产物的铂类和芳基金属抗癌药物研究进展

临床使用的现代药物超过50%都来自于天然产物,它们不仅能够通过阻止细胞周期进程、抑制癌细胞存活信号通路以及调节免疫细胞等多种生物途径来阻止肿瘤生长及其进程,而且对正常组织表现出较低的毒性。虽然以顺铂为代表的金属抗肿瘤药物广泛用于临床,但是它们存在严重的耐药性和毒副作用,包括肾毒性、神经毒性等。因此,利用天然产物中的优势来改造铂类配合物,有望开发出新型铂类抗癌药物以克服铂药的缺陷。另一方面,芳基金属配合物因其良好的水溶性和对正常组织的低毒性受到了广泛关注,将天然产物与芳基金属配合物相结合,也为开发高效低毒的新型抗癌药物提供了更多可能。结合天然产物和金属各自优势开发基于天然产物的金属配合物作为抗癌剂已成为研究热点,开辟了抗癌的新途径。本文对已经报道的有关天然产物的铂类和芳基金属配合物的研究及作用机理进行了较为全面的综述,并对该领域的未来发展进行了展望。     

手性药物的酶催化不对称定向合成

手性药物目前已成为国际上新药研究的热点。手性药物及其中间体的酶催化定向合成与传统的有机合成反应相比,所需条件温和,无需强酸强碱、高温高压等极端条件,可大大降低对设备的要求,同时具备反应速度快、立体选择性高等优势,而且对环境污染小,属于绿色合成技术,因而成为制备手性化合物的最有前景的方法之一。本文主要介绍了手性药物的酶催化不对称定向合成的方式、催化机理及应用,并引入了一些最新进展情况。     

Cinnamyl derivatives: synthesis and factor Xa (FXa) inhibitory activities

To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC(50) values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).     

A Synthetic Antithrombin III Binding Pentasaccharide Is Now a Drug! What Comes Next?

Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been used clinically as an antithrombotic agent since the 1940s. In the early 1980s it was discovered that a unique pentasaccharide domain in some heparin chains activates antithrombin III (AT-III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. Sanofi-Synthélabo and Organon developed a synthetic analogue of this pentasaccharide. The resulting antithrombotic drug arixtra, which went on the market in the USA and Europe in 2002, shows superior antithrombotic activity and brings about AT-III-mediated activity against factor Xa exclusively. Structure-based design has subsequently led to analogues with longer-lasting activity, such as idraparinux, as well as novel conjugates and long oligosaccharides with specific anti-Xa and antithrombin activities. The new drug candidates are more selective in their mode of action than heparin and less likely to induce thrombocytopenia.     

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities

Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.