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??OBJECTIVE To establish a population pharmacokinetic model of intravenous infusing busulfan in HSCT patients, and to explore physiological and pathological factors which may influence the pharmacokinetic parameters. METHODS We have collected clinical history information of 35 patients undergoing HSCT surgery and taking busulfan intravenous infusion for treatment. These information such as physiological and pathological factors and busulfan concentration data were used to perform the population pharmacokinetic analysis by applying the method of nonlinear mixed effects modeling(NONMEM).RESULTS A statistical model of busulfan is established,including variables such as body weight, sex, serum creatinine clearance. The success of 973 out of 1 000 times resampling trials (by bootstrap) shows that the newly parameters value are very close to the estimate value calculated from the final model by NONMEM, which demonstrates the established population pharmacokinetic model of busulfanis stable, effective and predictable. CONCLUSION The population pharmacokinetic model is established,which is capable of depicting the pharmacokinetic characteristics of busulfan . It is found that patients' weight, gender and creatinine clearance influence pharmacokinetic parameters, which can be useful and valuable for the clinical individualized dosing regimens.     

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??OBJECTIVE To study the hepatotoxicity of Polygonum multiflorum on the basic of the bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme. METHODS Inspected the enzyme kinetic parameters after giving the rats Polygonum multiflorum extract orally(in vivo), and added the Polygonum multiflorum extract into the human liver microsome(rat liver microsome; human recombinant UGT1A1 enzyme) to test the hepatotoxicity using the bilirubin as UGT1A1 enzyme substrate, investigating the inhibition of the UGT1A1 enzyme(in vitro). Apparent inhibition constant K_i and enzyme kinetic parameters were used to evaluate the hepatotoxicity. RESULTS Polygonum multiflorum extract has a strong inhibiton to the UGT1A1 enzyme in all the three systems in vitro. All the type of inhibition is the competitive inhibition. While Polygonum multiflorum extract has a strong inhibiton to the UGT1A1 enzyme in vivo, but the type of inhibition is the uncompetitive inhibition.CONCLUSION The method we had established in our study provides a new idea and a new method to evaluate the hepatotoxicity and the safety of Chinese herbs.     

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??OBJECTIVE To synthesize and evaluate of antihypertensive activity of novel nitric oxide-releasing N-phenyl-1H-pyrrole derivatives. METHODS By connecting key structural elements present in an AT1 receptor antagonist irbesartan with N-phenyl-1H-pyrrole carboxylic acid, a novel AT1 antagonist compound 4 was designed and synthesized, and a series of novel NO-donating derivatives (IN 1-10) were obtained by introducing NO donor. The amount of NO production in vitro of the target compounds were determined by Greiss assay. And the antagonism of Ang II induced vascular contraction assay was used to value the inhibition rate. RESULTS The antagonism of Ang ?? induced vascular contraction assay indicated that the novel compound exhibited similar activity as losartan. The NO derivative, compound IN9, found to release the maximum amount of NO during the NO releasing assay, was more potent than the lead compound 4 and positive control losartan. CONCLUSION These date indicate that the improved activities of these hybrid molecules contribute to the NO donor and the protection ability of NO donor make them promising candidates as antihypertensive agents.     

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??OBJECTIVE To explore the synthesis of novel phenylalanine dipeptide derivatives and their inhibitory effects on tumor cells. METHODS Starting from L-phenylalanine or L-tyrosine, a series of derivatives were synthesized by reaction with chloroacetyl chloride, followed by condensation with L-phenylalaninol or L-phenylalanine methyl ester hydrochloride and nucleophilic substitution reaction with differently substituted phenol.The cell proliferation inhibiting activities of the derivatives were evaluated by thiazolyl blue tetrazolium bromide(MTT)method.RESULTS Some of the target compounds showed certain inhibitory effect for leukemia cell lines K562 and HEL in vitro.Furthermore, the derivatives 3f and 3q had preferably inhibitory effect on K562 cell line prostate cancer PC3 cells in vitro.CONCLUSION Phenylalanine dipeptide derivatives possess good effect on the leukemia and prostate cancer cells and are worth of further research.     

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??OBJECTIVE To determine two toxic impurities, namely bromoacetic acid and 4-aminobenzonitrile, in the intermediate of dabigatran etexilate by UHPLC-MS. METHODS The separation was performed on a Shimadzu Shim-Pack GIS C₁₈ column (2.1 mm??50 mm,2 ??m) with mobile phase consisting of 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol (B) by gradient elution at a flow rate of 0.4 mL??min^-1. The detection was achieved by triple quadrupole mass spectrometry with rapid polarity switching using MRM mode. RESULTS The calibration curves were linear in the ranges of 0.2-40 and 0.4-40 ng??mL^-1 for bromoacetic acid and 4-aminobenzonitrile, respectively. The values of LOQ of bromoacetic acid and 4-aminobenzonitrile were 0.1 and 0.4 ng??mL^-1, respectively. The recoveries of bromoacetic acid and 4-aminobenzonitrile were 100.9% and 99.6%, respectively. CONCLUSION The method is accurate, rapid, sensitive, and reliable to determine the two toxic impurities bromoacetic acid and 4-aminobenzonitrile in the intermediate of dabigatran etexilate for quality control.     

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??OBJECTIVE To investigate the differences in the accumulation and biosynthesis of metabolites in different lactic acid of Pseudostellariae Radix. METHODS ¹H-NMR based metabolomic approach combined with multivariate statistical analysis was used to investigate the chemical compositions and find the different metabolites in cultivated Pseudostellariae Radix and its wild-type. RESULTS Thirty-five metabolites were identified in the ¹H-NMR spectra, and 15 of which showed remarkable differences. The multivariate statistical analysis showed that the cultivated Pseudostellariae Radix and its wild-type could be distinguished obviously. The contents of isoleucine, linolenic acid, lactic acid, alanine, lysine, glutamic acid, glutamine, acetoacetic acid, succinic acid, ??-aminobutyric acid, phenylalanine, and sucrose in cultivated Pseudostellaria heterophylla were lower than its wild-type, while the cultivated Pseudostellariae Radix contained more xylose, raffinose, and fumaric acid. CONCLUSION This study will provide basic information for exploring the quality formation mechanism and revealing the accumulation and biosynthesis of metabolites in different ecotypes of Pseudostellariae Radix.     

�����������ùAspergillus fumigatus YK-7����������л���Ｐ�俹���������о�

??OBJECTIVE To study the secondary metabolites of marine-derived fungus Aspergillus fumigatus YK-7. METHODS The compounds were isolated by several column chromatographic techniques, including silica gel, ODS, Sephadex LH-20 column chromatography, and HPLC, and their structures were identified on the basis of physicochemical properties and spectroscopic analysis. Trypan blue and MTT methods were applied for determining the effects of the compounds on proliferation of cancer cells in vitro. RESULTS Ten compounds were obtained, and their structures were identified as pseurotin A (1), pseurotin A₁(2), 14-norpseurotin A (3), FD-838 (4), demethoxyfumitremorgin C (5), 9??-hydroxyverruculogen TR-2 (6), 6-methoxyspirotryprostatin B (7), spiro[5H,10H-dipyrrolo[1,2-a:1??,2??-d]pyrazine-2-(3H),2??-[2H]indole]-3??,5,10(1??H)-trione (8), terezine D (9), and 14-hydroxyterezine D (10). CONCLUSION Compounds 3, 6, 7, 9, and 10 are isolated from marine-derived fungus Aspergillus fumigatus for the first time. Compounds 1-4 exhibite moderate antiproliferative activity against selected cancer cell lines in vitro.     

��ŵ���ض�1-�׻�-4-����-1,2,3,6-��������յ�C57BL/6С����Ϊѧ���˵����������о�

??OBJECTIVE To investigate the effect of minocycline on the behavior damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) in C57BL/6 mice. METHODS The PD models were formed with intraperitoneal injections of MPTP in C57BL/6 mice.Forty mice were randomly divided into 4 groupscontrol group,MPTP group,MPTP+Mino group and Mino group(10 for each group). The levels of midbrain DA,DOPAC and HVA were measured by HPLC after behavior tests(swimming test,pole test and locomotor activity test ) were performed. RESULTS Swimming scores,climbing score and locomotor activity of MPTP+Mino group were significantly higher than the MPTP group(P<0.01). And the content of midbrain DA,DOPAC and HVA of MPTP+Mino group was significantly higher than the MPTP group(P<0.01). CONCLUSION Minocycline inhibits MPTP-induced damage of motor function in mice,the mechanism may be work via inhibiting MPTP-induced mice dopamine neuron damage.     

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??OBJECTIVE To study the effect mechanism of tempol against hypobaric hypoxia-induced heart damage in mice. METHODS One hundred and ten BALB/c mice were randomly divided into normal control group, hypoxia model group, acetazolamide group and tempol group. After single intraperitoneal injection for 30 min, the mice were exposed to a simulated high altitude of 8 000 m for 12 h. After hypoxic exposure, blood was collected from the eye sockets and separated into serum to measure the activities of lactic dehydrogenase (LDH)and creatine kinase (CK). Then the mice were sacrificed and the content of H₂O₂ and malondialdehyde (MDA) as well as ATPase and antioxidant enzyme activity in heart were determined. HIF-1, VEGF, Nrf2, and HO-1 were detected by immunohistochemistry. RESULTS Compared with normal control group, the activities of plasma CK and LDH in hypoxia model group significantly increased. In addition, the content of H₂O₂ and MDA in hypoxia model group significantly increased while ATPase and antioxidant enzymes activity markedly decreased compared with the normal control group. Moreover, the expression of HIF-1??, VEGF, Nrf2 and HO-1 increased. Prior administration of tempol effectively decreased the activities of plasma CK and LDH as well as the content of H₂O₂ and MDA in heart tissue. Tempol could increase ATPase and antioxidant enzyme activities and decreased the expression of HIF-1?? and VEGF compared with hypoxia model, while it could further increase the expression of Nrf2 and HO-1. CONCLUSION Tempol has protective effect on heart injury induced by hypobaric hypoxia in mice. Its mechanism may be attributed to the amelioration of energy metabolism, scavenging free radical, improvement of antioxidant enzyme activity the activation of the Nrf2/HO-1 pathway as well as alleviation of oxidative stress.     

HPLC测定南葶苈子中槲皮素-3-O-β-D-葡萄糖-7-O-β-D-龙胆双糖苷的含量

目的:研究南葶苈子中槲皮素-3-O-β-D-葡萄糖-7-O-β-D-龙胆双糖苷的含量测定方法,建立南葶苈子药材质量标准.方法:采用反相高效液相色谱法,以自制标准品作对照,对南葶苈子药材中主要有效成分槲皮素-3-O-β-D-葡萄糖-7-O-β-D-龙胆双糖苷进行了含量测定.结果:回收率为99.78%,RSD为2.4%.结论:该方法可用于南葶苈子药材的质量控制.     

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??OBJECTIVE To synthesize the derivatives of 8-amino benzofuran[3,2-d]pyrimidine and study their anticancer activities.METHODS The target compounds were synthesized through a series of reactions, and their anticancer activities in vitro were evaluated against COLO205, MCF-7 and K562 cell lines by MTT as assay. RESULTS Nine title compounds were synthesized and confirmed by EI-MS,¹H-NMR and ¹³C-NMR.Compounds 2, 3d and 5c had good inhibition effect against COLO205, MCF-7 and K562 cells.The inhibition rates of compound 5c against COLO205, MCF-7 and K562 cells were 99.58%,78.75% and 98.68% respectively at 10^-4 mol??L^-1. CONCLUSION The anticancer activity of benzofuran[3,2-d] pyrimidine derivatives is worthy of further study.     

含有取代哌嗪及哌啶结构的噻吩并吡啶类化合物的合成及活性研究

 目的 设计合成一系列新型的含取代哌嗪及哌啶的噻吩并吡啶类衍生物,并对其体内抗血小板聚集活性进行了初步评价。 方法 从噻吩并吡啶 ( 1 ) 出发,与氯乙酰氯连接得到关键中间体（ 2 ）,再与一系列取代哌嗪及哌啶连接得到目标化合物（ 3-19 ）。 结果 得到 17 个新化合物,所有化合物结构都经过 ¹ H NMR 及质谱确证。这些化合物都进行了大鼠体内抑制血小板聚集活性测试。其中化合物 10-14 具有较高活性。 结论 该类噻吩并吡啶衍生物有可能成为新型结构的具有抗血小板聚集活性的先导化合物,值得进一步研究。     

7-(香豆素-3-甲酰胺)-3-[1-(取代）吡啶基甲基]头孢菌素的合成

 目的：探讨3'-乙酰氧基被N-7亲核试剂取代的反应条件、分离精制方法和新头孢菌素的体外抗菌活性。方 法：7-(香豆素-3-甲酰胺)头孢菌素在Nal或KSCN的存在下与吡啶和β-甲基吡啶反应，产物用大孔吸附树脂及葡 聚糖凝胶柱层析分离。结果：合成的二个新头孢菌素化合物，由红外光谱、元素分析和核磁共振谱确证其化学结构。体外抗菌试验表明，对某些革兰阴性菌有一定的抑菌作用。结论：该反应中加入大量的Nal可缩短短反应时间并减少杂质。大孔吸附树脂可有效果将头孢菌素与无机盐分离。     

7－（香豆素－3－甲酰胺）－3－［1－（取代）吡啶基甲基］头孢菌素的合成

目的：探讨３＇－乙酰氧基被Ｎ－亲核试剂取代的反应条件、分离精制方法和新头孢菌素的体外抗菌活性。方法：７－（香豆素－３－甲酰胺）头孢菌素在ＮａＩ或ＫＳＣＮ的存在下与吡啶和β－甲基吡啶反应，产物用大孔吸附树脂及葡聚糖凝胶柱层析分离。结果：合成的二个新头孢菌素化合物，由红外光谱、元素分析和核磁共振谱确证其化学结构。体外抗菌试验表明，对某些革兰阴性菌有一定的抑菌作用。结论：该反应中加入大量的ＮａＩ可缩短反应时间并减少杂质。大孔吸附树脂可有效地将头孢菌素与无机盐分离。     

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??OBJECTIVE To research the effect of new L-phenylalanine derivatives on acetylcholinesterase(AChE) activity. METHODS New L-phenylalanine derivatives were synthesized from substituted 2-bromo-1-acetophenones by four steps reaction, and their inhibitory activities on AChE were measured by Ellman method in vitro. RESULTS The evaluation results showed that most derivatives possessed AChE inhibitory effect and the activity of compound 8b was the most potent with an IC₅₀ value of 8.73??10^-6 mol??L^-1, which was more potent than that of rivastigmine; moreover, compound 8b had no inhibitory activities to BuChE. CONCLUSION The inhibitory activities of new L-phenylalanine derivatives on acetylcholinesterase are worth studying further.
     

Synthesis of [4,5-3H]-Exo-3,6-epoxyhexahydrophthatic anhydride

A convenient two-step synthesis of [4,5-³H]-Exo-3,6-epoxyhexahydrophthatic anhydride ((4,5-³H)-norcantharidin) consists of furan reacting with maleic anhydride to form dehydronorcantharidin. Then addition of tritium to dehydronorcantharidin with catalyst to form [4,5-³H]-norcantharidin. The specific activity and radiochemical purity were 56 Ci/mmol and 98%, respectively.     

C-3芳节叉基噻二唑并均三唑酮氧氟沙星衍生物的合成及抗肿瘤活性

目的发现氟喹诺酮由抗菌活性向抗肿瘤活性转化的有效结构修饰策略。方法基于药效团和骨架迁越药物设计原理,用均三唑杂环和α,β-不饱和酮分别作为C-3羧基的等排体和稠合修饰基,设计合成了C-3噻二唑并均三唑不饱和酮目标化合物(6a^61)。用元素分析和光谱数据确证化合物的结构,四甲基偶氮唑盐微量酶反应比色法(MTT)方法评价了目标化合物体外对SMMC-7721、Capan-1和HL603种癌细胞株的抗增值活性。结果合成了12个新结构的C-稠杂环不饱和酮化合物,体外抗肿瘤活性显著强于母体化合物1,其中含氟苯基和邻甲氧苯基化合物的活性与对照抗肿瘤药多柔比星相当。结论噻二唑并均三唑不饱和酮骨架替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。     

3-芳苄叉基噻唑酮-氟喹啉-4-酮氧氟沙星衍生物的合成及抗肿瘤活性

目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。     

N-[2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基]-N′-(4-取代苯基)-3(2H,4H)-1,2,4-三唑酮的合成和抗真菌活性

目的寻找广谱、高效、低毒的新一代三唑类抗真菌药物。方法根据靶酶活性位点的空间特征、各种力场和关键残基分布,设计并合成了N-[2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基]-N-′(4-取代苯基)-3(2H,4H)-1,2,4-三唑酮类化合物,并测定了体外抗真菌活性。结果体外抑菌测试结果表明,目标化合物对8种致病真菌均有一定程度的抗真菌活性,对深部真菌的活性明显优于浅部真菌。结论目标化合物对白色念珠菌均显示有较强的体外抗真菌活性,化合物1具有广谱、高活性的优点,值得进一步结构优化。