Crystal Structures of 2-Aminobenzothiazole-based Inhibitors in Complexes with Urokinase-type Plasminogen Activator

Urokinase-type plasminogen activator （uPA） plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer therapy. Most current uPA inhibitors employ a highly basic group （either amidine or guanidine group） to target the S1 pocket of uPA active site, which leads to poor oral bioavailability. Here we study the possibility of using less basic 2-aminobenzothiazole （ABT） as S1 pocket binding group. We report the crystal structures of uPA complexes with ABT or 2-amino-benzothiazole-6-carboxylic acid ethyl ester （ABTCE）. The inhibitory constants of these two inhibitors were measured by a chromogenic competitive assay, and it was found that ABTCE is a better inhibitor for uPA （Ki = 656 μM） than ABT （Ki = 5.03 mM）. This work shows that 2-amniobenzothiazole can be used as P1 group which may have better oral bioavailability than the commonly used amidine or guanidine group. We also found the ethyl ester group occupies the characteristic oxyanion hole and contacts to uPA 37- and 60-loops. Such work provides structural information for further improvements of potency and selectivity of this new class of uPA inhibitor.

Synthesis and Crystal Structure of Trans-4-[(5-(2,4-Dichlorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyleneamino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one

The title compound trans-4-[（5-（2,4-dichlorophenoxy）-3-methyl- 1-phenyl-1H-pyrazol-4-yl）methyleneamino]- 1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 3 （C28H23Cl2N5O2, Mr = 532.41） has been synthesized and its crystal structure was determined by single-crystal X-ray diffraction analysis. It crystallizes in triclinic, space group P1- with a = 8.9438（4）, b = 11.6065（5）, c = 14.2215（6）A, α = 112.566（1）, β = 92.324（2）, γ = 102.91（1）°, V= 1315.65（10） A^3, Z = 2, Dc = 1.344 g/cm^3,μ（MoKa） = 0.282 mm^-1, λ = 0.71073 A, F（000） = 552, the final R = 0.0587 and wR = 0.1578 for 5071 observed reflections （I 〉 2σ（I））. X-ray analysis reveals that the product is a thermodynamically stable trans isomer. Intra- and intermolecular C（ 12）-H（12）…O（1） and C（28）-H（28）...O（1）# 1 hydrogen bonds were observed in the title compound.

2D-QSAR Studies on Pyrazole Compounds Containing Pyrimidine Amino

The quantitative structure-activity relationship （QSAR） of 16 pyrazole compounds was studied by ab initio method at the HF/3-21G level using Guassian03 soft. The optimized structures together with some characteristic and electric parameters of the title compounds were obtained; some stereo-parameters were calculated by HyperChem software. Stepwise multiple regression method was adopted to establish bi- and tri-parametric models between biological activity and some parameters. The lager △E and logP, the higher biological activity; and the biological activity would be promoted with the smaller μ, QN and QPYRA. It provided a theory direction to synthesize some compounds with high activity.

PMBP缩2-氨基苯并噻唑席夫碱/离子液体双水相体系萃取废水中重金属离子的研究

合成了新型萃取剂1-苯基-3-甲基-4-苯甲酰基-吡唑啉酮-5缩2-氨基苯并噻唑席夫碱(PMBP-2-ABT),并以其为萃取剂,建立了一种用PMBP-2-ABT/离子液体双水相体系萃取重金属离子的新方法。考察了影响萃取效果的各种因素,如金属离子种类、pH值、萃取剂浓度等。结果表明:该萃取体系对重金属离子的萃取能力由强到弱的顺序为:Cu2+、Pb2+、Co2+、Ni2+、Zn2+;离子液体双水相体系中PMBP-2-ABT是萃取重金属离子的良好萃取剂。

新型2-苯并噻唑磺酰脲氨基酸及其甲酯衍生物的合成与抗肿瘤活性

以2-巯基苯并噻唑为原料,经弱氧化和氨化制得2-苯并噻唑次磺酰胺(2);2经高锰酸钾氧化制得2-苯并噻唑磺酰胺(3);3与氯甲酸乙酯反应制得2-苯并噻唑磺酰胺甲酸乙酯(4);4与L-氨基酸甲酯反应制得一系列2-苯并噻唑磺酰脲氨基酸甲酯(6a^6j);6经水解合成了10个新型的2-苯并噻唑磺酰脲氨基酸(7a^7j),其结构经~1H NMR,IR和ESI-MS表征。并研究了6和7对Cdc25B的抑制活性。结果表明:在用药浓度为20μg·m L^(-1)时,6c,6j,7d,7h和7j对Cdc25B抑制活性较好,抑制率分别为78.1%,71.2%,65.6%,57.2%和65.9%。

“一锅法”合成2-氨基苯并噻唑的工艺研究

以苯胺为原料,采用"一锅法"直接合成2-氨基苯并噻唑,研究并获得了最佳工艺条件。该方法避免了通过合成苯基硫脲后再合成产品的两个环节,具有工艺过程简单,环境污染较小,经济效益高等优点。小试实验结果表明,在最佳工艺条件下,产品的合成收率达到84%。

“一锅法”合成2-氨基-4-甲基苯并噻唑的工艺研究

以邻甲苯胺为原料,采用"一锅法"直接合成2-氨基-4-甲基苯并噻唑,获得了最佳工艺条件。该方法避免了通过合成N-邻甲苯基硫脲后再合成产品的两个环节,具有工艺过程简单,操作方便的优势。放大实验结果表明,在最佳工艺条件下,产品的平均收率达到了88%。

LC-MS^n测定2-[[(2′-氰基联苯基)-4-基]甲基]氨基-3-硝基苯甲酸乙酯中的不纯物

The impurities in ethyl-2-[[2′-cyanobiphenyl-4-yl] methyl] amino]-3-nitrobenzoate,an intermediate for synthesis of candesartan cilexiti,were detected by LC-MSn. The structural assignment of these impurities was carried out by LC-MSn using electrospray ionization source and an ion trap mass analyzer. The formation of the impurities was discussed. Also the fragmentation pathways of these compounds were studied.

6-取代苯并噻唑-2-氨基硫代磷酸二烷基酯的合成

用 6-位取代的 2 -氨基苯并噻唑与三氯硫磷反应 ,合成了 3个苯并噻唑 -2 -氨基硫代磷酰二氯 ,并由此合成了 9个苯并噻唑 -2 -氨基硫代磷酸二烷基酯 .讨论了苯并噻唑环上取代基对反应的影响和产物中硫代磷酸酯的烷基的空间效应对反应的影响 .所合成的部分化合物对人喉鳞状细胞癌 ( Hep-2 )具有一定的抑制能力 .

光谱法测试瓜环与2-氨基苯丙噻唑的主客体作用

利用1H NMR技术,紫外吸收光谱法和荧光光谱法考察了七、八元瓜环(cucurbit[n]urilsn=7,8)与2-氨基苯并噻唑(g)的相互作用。实验结果表明:在2<pH<9范围内,利用不同的光谱方法均能观察到瓜环与客体的相互作用;Q[7]与客体作用形成物质的量比为1∶1的包结配合物,Q[8]与客体形成物质的量比为1∶2的包结配合物,并计算出包结常数,同时测试了超分子体系的热力学稳定性及熵变,焓变。

2-氨基苯并噻唑锌配合物对棉铃虫生长发育的影响

选取数百条正常三龄棉铃虫,分成5组,分别饲喂含不同剂量的2-氨基苯并噻唑锌配合物的人工配制饲料,期间测量每条虫的体重,直至生长到六龄使用血细胞计数板对血细胞进行计数,再测定血浆中的T-SOD活性.结果显示:与对照组相比,饲喂含低剂量2-氨基苯并噻唑锌配合物饲料的棉铃虫的血细胞数目较多,T-SOD活力较强;饲喂含高剂量配合物饲料的棉铃虫受到严重抑制,几乎处于不生长状态.以上结果表明低剂量2-氨基苯并噻唑锌配合物对棉铃虫生长发育有促进作用,而高剂量的则有抑制作用.

2-氨基-苯并噻唑水解制备2-氨基苯硫酚的研究

以2-氨基-苯并噻唑为原料水解制备2-氨基苯硫酚,对反应中间体S-甲酰基-2-氨基苯硫酚进行了分离和结构确认,在此基础上对反应机理进行分析,采用新的分步水解方案使总收率达到95.4%。

SYNTHESIS,CHARACTERIZATION AND ANTIMICROBIAL PROPERTIES OF 4-[(4-HYDROXYBENZYLIDENE)AMINO]PHENOL AND ITS POLYMER

The oxidative polycondensation reaction conditions of 4-[（4-hydroxybenzylidene） amino] phenol （4-HBAP） were studied with H2O2, air oxygen and NaOCl in an aqueous alkaline medium between 50 and 90℃. The structures of the obtained monomer and polymer were confirmed by FT-IR, UV-Vis, 1H- and 13C-NMR and elemental analysis. The characterization was made by TG-DTA, size exclusion chromatography （SEC） and solubility tests. At the optimum reaction conditions, the yield of poly[4-（4-hydroxybenzylidene amino） phenol] （P-4-HBAP） was found to be 48.3% （for H2O2 oxidant）, 80.5% （for air O2 oxidant） and 86.4% （for NaOCl oxidant）. According to the SEC analysis, the number-average molecular weight （Mn）, weight-average molecular weight （Mw） and polydispersity index （PDI） values of P-4-HBAP was found to be 8950, 10970 g tool^-1 and 1.225, respectively, using H202; and l l610, 15190 g tool^-1 and 1.308 respectively, using air 02 and 7900, 9610 g mol^-1 and 1.216, respectively, using NaOC1. According to TG-DTA analyses, P-4-HBAP was more stable than 4-HBAP against thermal decomposition. The weight loss of P-4-HBAP was found to be 49.27% at 1000℃. The highest occupied molecular orbital （HOMO） and the lowest unoccupied molecular orbital （LUMO） values calculated from electrochemical measurement. Electrochemical energy gaps （Eg＇） of 4-HBAP and P-4-HBAP were found to be -5.46, -5.28; -2.26, -2.67; 3.20 and 2.61 eV, respectively. According to UV-Vis measurements, optical band gap （Eg） of 4-HBAP and P-4-HBAP were found to be 3.34 and 3.01 eV, respectively. Also, antimicrobial activities of 4-HBAP and P-4-HBAP were examined against selected some bacteria. The electrical conductivity of the polymer was measured after doping with iodine.

4-AHBA为核的聚芳醚树枝状化合物的合成及其光学性能

合成了三个新的以2-(4-氨基-2-羟基苯基)苯并噻唑(4-AHBA)为核的聚芳醚树枝状化合物(1a^1c),其结构由1HNMR,13C NMR,IR,MS和元素分析表征。研究了1和4-AHBA在氯仿中的紫外吸收光谱和荧光发射光谱,结果表明,1与4-AHBA相比,紫外吸收强度大大提高,且最大吸收波长从349 nm红移至352 nm,荧光最大发射强度增强26倍~29倍。

All-optical switching and nonlinear optical properties of HBT in ethanol solution

This paper demonstrates an all-optical switching model system comprising a single pulsed pump beam at 355 nm and a CW He-Ne signal beam at 632.8 nm with 2-（2＇-hydroxyphenyl）benzothiazole （HBT） in ethanol solution. The origins of the optical switching effect were discussed. By the study of nonlinear optical properties for HBT in ethanol solvent, this paper verified that the excited-state intramolecular proton transfer （ESIPT） effect of HBT and the thermal effect of solvent worked on quite different time scales and together induced the change of the refractive index of HBT solution, leading to the signal beam deflection. The results indicated that the HBT molecule could be an excellent candidate for high-speed and high-sensitive optical switching devices.

Syntheses, Crystal Structures and DNA-binding Properties of Zn(Ⅱ), Ni(Ⅱ) and Co(Ⅱ) Compounds Containing Thiazole Derivatives

Zn(Ⅱ), Ni(Ⅱ) and Co(Ⅱ) compounds(1～3) based on 2-(2-pyridyl)benzothiazole(bpt) and terephthalic acid(PTA) were synthesized. The crystal structures of [Zn(bpt)(PTA)2](1), [Ni(bpt)(PTA)2](2), and [Co(bpt)(PTA)2](3) have been determined by single-crystal X-ray diffraction analysis, which shows that all the three complexes belong to monoclinic system with space group P21/c. Time-dependent density functional theory(TD-DFT) calculation is performed on a reference structure of compound 3. The excited electrons mainly localized at the π* of ligand 2-(2-pyridyl)benzothiazole, which will be convenient for them to bind with the DNA reacting sites. Fluorescence spectroscopy, ultraviolet(UV) spectroscopy and viscosity were used to characterize the interaction of the compounds with Calf thymus DNA(CT-DNA). The results indicate that compounds 1～3 bind to CT-DNA and have a strong interaction with DNA. The compounds can probably bind to CT-DNA via a non-intercalative mode as concluded by studying the viscosity of a DNA solution in the presence of the compounds. This combination can effectively break DNA, which speculates that these three compounds may interact with the cancer cell DNA in this binding mode, thereby damaging the cancer cells.

Synthesis, Antibacterial Activities and Nuclease Properties of Ternary Copper（II） Complex Containing 2-（2＇-Pyridyl）benzothiazole and Glycinate

A new ternary complex [Cu（PBT）（Gly）（H2O）]ClO4 （PBT=2-（2＇-pyridyl）benzothiazole, and Gly=glycinate） has been synthesized and characterized by elemental analysis, molar conductivity, and IR methods. The complex, structurally characterized by single-crystal X-ray crystallography, shows a slightly distorted square-pyramidal coordination geometry in which two nitrogen atoms of PBT and the carboxylate oxygen atom O and the amino nitrogen atom N of Gly bind at the basal plane, a water molecule is coordinated at the apical position. The complex, Cu（ClO4）2 and flee PBT were each tested for their ability to inhibit the growth of two Gram（--） （Escherichia coil, Salmonella） and two Gram（＋） （Bacillus subtilis, Staphylococcus aureus） microorganisms. The complex showed good antibacterial activities against the microorganisms compared with free PBT and Cu（C104）2. The interaction between the complex and calf thymus DNA in aqueous solution was investigated using electronic spectroscopy, fluorescence spectroscopy, circular dichroic spectroscopy, and viscosity measurements. Results suggest that the complex could bind to DNA by an intercalative mode. In addition, the result of agarose gel electrophoresis showed that the complex can cleave the plasmid DNA by hydroxyl radicals and singlet oxygen-like species under the condition of physiological pH and room temperature.

Effect of protease inhibitor from Agaricus bisporus on glucose uptake and oxidative stress in 3T3-L1 adipocytes

Objective:To explore the effect of the protease inhibitor from Agaricus bisporus(J.E.Lange)Imbach(AbPI)on glucose uptake and oxidative stress in 3 T3-L1 adipocytes.Methods:Adipocytes were differentiated and stained with OilRed-O staining to confirm adipogenesis.The toxic/protective effect of AbPI on the adipocytes was determined by MTT assay,intracellular reactive oxygen species generation through flow cytometry,and morphologically through confocal microscopy using propidium iodide,4,6-diamino-2-phenylindol dihydrochloride,and 2’,7’-dichlorofluorescein diacetate dyes.The uptake of fluorescent glucose analog,2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose by adipocytes was also studied through confocal microscopy.Results:MTT assay showed that the cell survival rate was(28.00±3.00)%,(92.33±2.60)%,and(71.34±2.10)%in the presence of 2 mM H2O2,AbPI alone,and AbPI and H2O2 both,respectively,in comparison to the control.Oil-Red-O staining indicated that Ab PI enhanced adipogenesis.AbPI stimulated the glucose uptake by adipocytes similar to the drug rosiglitazone,and showed insulinsensitizing effect in the presence of insulin,but failed to stimulate the uptake in the absence of insulin.Intracellular reactive oxygen species generation was reduced in differentiating adipocytes upon Ab PI treatment.Confocal microscopy showed that the damaged cell population rose to 3.50%,117.84%,and 261.50%in the presence of Ab PI alone,AbPI with H2O2,and H2O2 alone,respectively.Conclusions:The protease inhibitor enhances glucose uptake by adipocytes and exhibits a cytoprotective effect on them.

Lipophilicity determination of N-( benzothiazol-2-yl )-α-amino alkyl phosphonic diesters by RP-HPLC and RP-HPTLC

Using methanol-water mixtures as the mobile phase, the chromatographic retention parameters k' and Rf were determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and reversed-phase high-performance thin-layer chromatography (RP-HPTLC) for N-(benzothiazol-2-yl)-α-amino alkyl phosphoric diesters and the correlation with lipophilicity parameter (Clog P) was established. Log Kw values obtained from RP-HPLC and Rm values obtained from RP-HPTLC can be used to evaluate the lipophilicity of this kind of compounds. Chromatographic method is a good alternative for lipophilicity measurement.

谷氨酸释放抑制剂riluzole对弥漫性脑损伤的保护作用

目的 探讨谷氨酸释放抑制剂 2 -氨基 - 6 -三糖甲氧苯噻唑 (riluzole)对大鼠弥漫性脑损伤的保护作用及其机制 .方法 在自由落体致弥漫性脑损伤模型的基础上 ,通过测定脑组织含水量、谷氨酸、TXB2 ,6 - keto- PGF1α,c AMP,c GMP等水平变化 ,以及应用硝酸镧标记电镜分析观察血脑屏障的通透性改变 ,评价 riluzole对弥漫性脑损伤的保护作用 .结果 应用 riluzole组大鼠在脑创伤后早期脑组织含水量和谷氨酸水平明显下降 ;TXB2 ,6 - keto- PGF1 α水平和 TXB2 / 6 - keto-PGF1α比值下降 ,而 c AMP/ c GMP比值回升 ;硝酸镧标记电镜显示通过毛细血管渗透到脑组织中的硝酸镧沉淀颗粒减少 ,血脑屏障的通透性下降 .结论 Riluzole对大鼠弥漫性脑损伤具有保护作用 ,是通过抑制谷氨酸释放 ,影响脑组织细胞内外离子平衡和渗透压 ,降低血脑屏障通透性 。