非肽类凝血酶抑制剂的比较分子力场分析

在血栓症和止血疗法中凝血酶起重要的生物调节作用，凝血酶抑制剂由于基溶 血栓作用成为药物设计的热点，对非肽类芳基磺酸酯系列凝血酶抑制剂进行了三维 定量构效关系研究。用Autodock方法和比较分子力场分析相结合构建了该类分子的 定量构效关系模型，得到三维等值线图。模型的传统相关系数r~2=0.956，交叉验 证系数q~2=0.681, F_(4,16) = 85.985，标准偏差S = 0.158。该模型为凝血酶抑 制剂的进一步结构改造提供了有益的启示。     

吡啶并嘧啶衍生物抗乳腺癌活性的CoMFA模型

基于比较分子力场分析(CoMFA)方法建立25种吡啶并嘧啶衍生物抗乳腺癌活性(pIC)的三维定量构效关系(3D-QSAR)。训练集中20个化合物用于建立预测模型,测试集6个化合物(含模板分子)作为模型验证。已建立的CoMFA模型的交叉验证系数(R_(cv)~2)、非交叉验证系数(R~2)分别为0.467、0.891,说明所建模型具有较强的稳定性和良好的预测能力。该模型中立体场、静电场对pIC的贡献率依次为40.8%、59.2%。基于此研究结果,设计了4个具有较高抗乳腺癌活性的新化合物,有待医学实验验证。     

新型苯并噻(噁)唑酮衍生物抑制黄瓜炭疽菌活性的QSAR研究

基于原子类型电性拓扑指数(Es),建立新型苯并噻(噁)唑酮衍生物对黄瓜炭疽菌杀菌活性的定量构效关系模型。通过最佳变量子集回归建立了它们的最佳三元(E_(31)、E_(42)、E_(32))QSAR模型,其判定系数(R~2)为0.863,逐一剔除法交叉验证相关系数(R_(cv)2)为0.677,估计标准误差(R_(MS))为4.198。经R_(cv)2、V_(IF)、F_T、A_C等检验,该模型具有良好的稳健性及预测能力。结果显示,与杀菌活性相关的3个Es描述子对应结构碎片分别为硫醚键(-S-)、共轭硫醚键(a-S-a)和氟键(-F),其中-S-结构碎片与杀菌活性呈负相关关系,而a-S-a、-F则与杀菌活性呈正相关关系。     

基于人工神经网络研究芳胺喹唑啉衍生物的抗胃癌活性

基于分子电性距离矢量(M_t)表征21个芳胺喹唑啉衍生物的分子结构,并与其对人胃癌细胞的抗癌活性(pI)关联。通过最佳变量子集回归方法建立上述化合物抗胃癌活性的三参数(M_(15)、M_(18)、M_(82))定量构效关系模型。其交叉验证系数(R_(cv)~2)、非交叉验证系数(R~2)依次为0.386和0.737。通过R、R_(cv)~2、V_(IF)等检验,模型具有较好的相关性、稳健性和预测能力。结果显示,-CH_2-、-CH、-O-、-S-和-NH-等分子结构单元直接影响这些化合物的抗胃癌活性。将M_(15)、M_(18)、M_(82)作为人工神经网络的输入层结点,采用3∶3∶1的网络结构,利用BP算法获得了令人满意的pI模型,其R~2和标准偏差S_D分别为0.992和0.080,表明pI与三参数呈现优异的非线性关系。     

糖原合成激酶-3β马来酰胺类抑制剂构效关系的理论研究

建立糖原合成激酶-3β(GSK-3β)抑制剂的三维构效关系,可预测新的糖原合成激酶-3β抑制剂.通过确定分子的药效构象,与选定的模板分子进行叠合,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)分别建立38个糖原合成激酶-3β抑制剂的3D-QSAR模型.比较分子力场分析法所建立的模型的决定系数q2=0.711,非交叉验证系数r2=0.887,标准偏差ES=0.411,显著系数F=109.856;比较分子相似性指数分析法所建立模型的决定系数q2=0.605,非交叉验证系数r2=0.931,标准偏差ES=0.326,显著系数F=122.122.该模型在一定程度上反映了结合部位的性质要求,解释马来酰胺类抑制剂的构效关系,具有较好的预测能力.     

二肽肽酶Ⅳ抑制剂的三维定量构效关系研究

二肽肽酶Ⅳ是一类用于治疗Ⅱ型糖尿病具有潜在价值的关键酶,很多此类酶的抑制剂用于处理此病具有相当好的有效性.一系列N-取代的甘氨酰氰基吡咯烷衍生物对于二肽肽酶具有高的活性和选择性.我们使用比较分子力场分析方法建立DPP-Ⅳ抑制剂--N-取代的甘氨酰氰基吡咯衍生物的三维定量构效关系,该模型为设计用于治疗Ⅱ型糖尿病的高效DPP-Ⅳ抑制剂提供结构信息.CoMFA模型的交叉验证相关系数q2=0.575,非交叉验证相关系数r2=0.981,绝对误差S=0.184,F9.68=388.5.使用七个预测集检验了模型的预测能力.所得的模型解释了已有的构效关系,并对同类化合物有较好的预测能力,该模型可用于指导新型的DPP-Ⅳ抑制剂的设计与优化.     

拓扑异构酶Ⅰ抑制剂高喜树碱类化合物的三维定量构效关系研究

针对拓扑异构酶Ⅰ抑制剂高喜树碱类化合物,采用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)的方法对其进行三维定量构效关系的研究.构建CoMFA模型其q2=0.706,最佳主成分数n=6,非交叉验证系数r2=0.966,标准差S=0.277,F=117.613,立体场和静电场的贡献值分别为0.62和0.38.构建CoMSIA模型其q2=0.696,最佳主成分数n=7,非交叉验证系数r2=0.956,标准差S=0.320,F=74.374,其疏水场和立体场的贡献分别为0.75和0.25.结果显示疏水场和立体场对化合物的活性有较大影响.     

MMPs抑制剂咖啡酸苯乙酯衍生物的3D-QSAR及分子对接研究

MMP-2是基底膜降解的关键酶,参与宫颈癌病发的整个过程,被认为是治疗宫颈癌的潜在新靶点。本文采用三维定量构效关系(3D-QSAR)研究32个咖啡酸苯乙酯类化合物与抗宫颈癌肿瘤细胞增殖活性的构效关系,通过比较分子场分析(CoMFA)模型(Q~2=0.638,R~2=0.972)及分子相似性指数分析(CoMSIA)模型(Q~2=0.665,R~2=0.975),表明所建立的QSAR模型具有稳定的预测能力。基于上述两种模型设计了18种新型咖啡酸苯乙酯类抑制剂,其中5种化合物具有较好的抗癌活性,抑制活性最强的为WS-1。将WS-1与MMP-2蛋白结合,结合模式显示WS-1主要通过氢键作用及疏水作用与MMP-2蛋白紧密结合,并能有效地占据MMP-2蛋白的结合位点。本研究构建的3D-QSAR模型也为进一步设计治疗宫颈癌其他抑制剂提供了理论参考。     

酪醇酯衍生物抗氧化活性的QSAR研究

抗氧化剂是防止食品氧化、提高食品稳定性的一类食品添加剂。为了研究25种酪醇酯衍生物对Fe~(3+)-TPTZ配合物抗氧化活性Fr的定量构效关系(QSAR),按照分子的拓扑环境编程计算了上述化合物的电性距离矢量(M_d)。通过最佳子集变量回归方法,建立了抗氧化活性的三参数(M_(32)、M_(59)、M_(77))QSAR模型,传统相关系数(R~2)与逐一剔除法交叉验证相关系数(R_(cv)~2)分别为0.939、0.815。经R_(cv)~2、V_(IF)、F_(IT)、A_(IC)、F诊断,显示良好的稳健性和预测能力。根据进入模型的3个变量可知,影响酪醇酯衍生物对Fe~(3+)-TPTZ配合物抗氧化活性的主要结构基团是酚羟基、C-和-NH-等。     

STAT3环烷烃并噻吩类衍生物抑制剂的三维定量构效关系研究

本文对STAT3抑制剂的化学结构与生物活性之间的关系进行研究。采用三维定量构效关系(3D-QSAR)中的比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法针对52个STAT3抑制剂建立3D-QSAR模型,阐明了抑制剂化学结构与其生物活性之间的关系。所构建的CoMFA模型交叉验证系数为0.548,非交叉验证系数为0.754,标准偏差为0.278,显著系数为58.297;所构建的CoMSIA模型交叉验证系数为0.892,非交叉验证系数为0.597,标准偏差为0.192,显著系数为57.794。结果显示CoMFA和CoMSIA模型具有良好的稳定性和预测能力。3D-QSAR模型等势图提供的相关场信息对新型STAT3抑制剂的设计具有指导意义。     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.     

Facile synthesis of bicyclic 1-arylpyrazol-5-ones

In this Letter, we described a facile method for constructing fused bicyclic 1-arylpyrazol-5-one ring system. We employed various methylene-containing carboxylic acids as the substrates and proved that the pyrazolone ring closure requires activated methylene group in intermediate II. Accordingly, a series of structurally diversified, fused bicyclic 1-arylpyrazol-5-ones was prepared in moderate to high yields using the requisite substrates.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

KMnO4-mediated oxidative CN bond cleavage of tertiary amines: Synthesis of amides and sulfonamides

KMnO₄-mediated oxidative CN bond cleavage of tertiary amines producing secondary amine was introduced, which was trapped by electrophiles (acyl chloride and sulfonyl chloride) to form amides and sulfonamides. The reaction could take place at mild condition, tolerating a wide range of function groups and affording products in moderate to excellent yields.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.