The search for a new model structure of β-Factor XIIa

We present the search for a new model of -factor XIIa, a blood coagulation enzyme, with an unknown experimental 3D-structure. We decided to build not one but three different models using different homologous proteins as well as different techniques and different modellers. Additional studies, including extensive molecular dynamics simulations on the solvated state, allowed us to draw several conclusions concerning homology modelling, in general, and -factor XIIa, in particular.     

以β-环糊精及其衍生物为手性选择剂毛细管电泳拆分几种药物的旋光对映体

在毛细管电泳中，采用β－环糊精（β－ＣＤ）及其衍生物为手性选择剂对扑尔敏、异丙嗪、二氧异丙嗪和氧氟沙星对映体进行了分离。优化了分离条件；讨论了环糊精空腔边缘与溶．质分子作用的基团的种类和分离效果的联系，通过计算手性分离的热力学常数比较了不同手性选择剂对扑尔敏对映体的分离能力。最后，讨论了乙腈在手性分离中的作用。     

Toward breast cancer resistance protein (BCRP) inhibitors: design, synthesis of a series of new simplified fumitremorgin C analogues

In this study, we report the design and synthesis of a series of new simplified fumitremorgin C analogues. The preliminary biological study indicated some of these simplified fumitremorgin C might be developed into breast cancer resistance inhibitors.     

N-环丙甲基-7α-[(R)-1-羟基-1-甲基-3-(2-噻吩)丙基]-6,14-内乙基桥四氢去甲基蒂巴因(噻诺啡)合成和晶体结构

N-环丙甲基-7α-[(R)-1-羟基-1-甲基-3-(2-噻吩)丙基]-6,14-内乙基桥四氢去甲基蒂巴因(噻诺啡)是阿片受体部分激动剂.噻诺啡经过一步法合成其结构通过单晶X射线衍射分析确证,其结构保持吗啡"T"型主体结构.     

Differential protonation and dynamic structure of doxylamine succinate in solution using 1H and 13C NMR

A protonation and dynamic structural study of doxylamine succinate, a 1:1 salt of succinic acid with dimethyl-[2-(1-phenyl-1-pyridin-2-yl-ethoxy)ethyl]amine, in solution using one- and two-dimensional 1H and 13C NMR experiments at variable temperature and concentration is presented. The two acidic protons of the salt doxylamine succinate are in 'intermediate' exchange at room temperature, as evidenced by the appearance of a broad signal. This signal evolves into two distinct signals below about -30 degrees C. A two-dimensional 1H-1H double quantum filtered correlation experiment carried out at -55 degrees C shows protonation of one of the acidic protons to the dimethylamine nitrogen. A two-dimensional rotating frame 1H-1H NOE experiment at the same temperature reveals that the other proton remains with the succinate moiety. Comparison of the 1H and 13C chemical shifts and the 13C T1 relaxation times of the salt with those of the free base further substantiate the findings.     

Chiral separation of the four stereoisomers of a novel antianginal agent using a dual cyclodextrin system in capillary electrophoresis

Reported here is an analytical method enabling the stereochemical resolution of a new antianginal compound possessing two stereogenic centers, leading to four stereoisomers. Only one of these isomers is currently under development as a novel antianginal agent and consequently, the other three isomers are considered as unwanted chiral impurities. Therefore, an enantioselective method is required in order to check its enantiomeric purity. This paper presents a method exploiting the high efficiency of capillary electrophoresis and the complexing properties of cyclodextrins to achieve the separation of the four stereoisomers of this weakly basic compound (pKa = 7.4). For this purpose, the combination of a neutral cyclodextrin, hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), and an anionic cyclodextrin, carboxymethyl-beta-cyclodextrin (CM-beta-CD), was added to the separation buffer running in an uncoated silica capillary. After selection of the suitable cyclodextrin system, satisfactorily separation conditions were as follows: 30 mM phosphate buffer (pH 6.4) containing 10 mM of HP-gamma-CD and 10 mM of CM-beta-CD, running voltage +30 kV. The resulting run time and resolutions were respectively about 17 min and between 1.95 and 2.84. Linearity curves (0.993 < r2 < 0.998) are also shown.     

Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. Conformational sampling of the protein-ligand complex is performed by molecular dynamics (MD) in vacuo and the solvent effect is calculated a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory. The binding free energy is written as a linear combination of the buried surface upon complexation, SASbur, the electrostatic interaction energy between the ligand and the protein, Eelec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, deltaGsolv. The method uses the buried surface upon complexation to account for the non-polar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy. The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure. A correlation coefficient of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol. When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calculated binding free energy and the experimental pIC5o without reparametrization.     

高效液相色谱-电喷雾质谱(HPLC-ESI-MS/MS)测定新型抗癌铂配合物

采用高效液相色谱-电喷雾-多级质谱法(HPLC-ESI-MS/MS), 研究了cis-3,5-diisopropylsalylic cyclohexanodiaminoplatinum(Ⅱ)的电喷雾质谱行为, 鉴定了其杂质, 并测定了其纯度.     

尿中MDMA和MDA的酰基衍生化-氮磷检测气相色谱分析法

研究了致幻性安非他明类药物3,4-亚甲二氧基甲基安非他明(MDMA)和3,4-亚甲二氧基安非他明(MDA)的乙酰化、三氟乙酰化、五氟丙酰化、七氟丁酰化、二氯乙酰化、一氯二氟乙酰化、五氟苯甲酰化、五氟苯磺酰化和二硝基苯甲酰化的衍生化反应条件,发现除了乙酰化之外所研究的各种衍生化反应均可用5μL酸酐或酰氯在环己烷中于20℃10 m in内完成。乙酰化可用20μL乙酸酐在60℃30 m in内完成。在此基础上建立了尿中MDMA和MDA的各种衍生化的氮磷检测气相色谱(GC/NPD)分析方法。方法操作简便快速,绝大多数方法的检出限低于10μg/L,其中二氯乙酰化、一氯二氟乙酰化、五氟苯甲酰化、五氟苯磺酰化和二硝基苯甲酰化的GC/NPD分析方法未见文献报道。对一些灵敏的方法进行了线性关系和回收率的考察,结果满意。