用电喷雾离子阱质谱法对SFZ-47在家兔体内两主要代谢物的分析

以ＨＰＬＣ对家兔单剂量口服１００ｍｇ新抗炎镇痛剂ＳＦＺ ４７［３Ｈ １,２二氢 ２ （４ 甲基苯胺基）甲基 １ 吡咯里嗪酮］后尿中的两主要代谢物进行了分离、制备,再用电喷雾离子阱质谱法对代谢物分别进行结构鉴定．结果表明,采用负离子ＥＳＩ ＭＳ３检测方式,对代谢物ＳＦＺ ４７羧基衍生物［４ （３Ｈ １,２ 二氢 １ 吡咯里嗪酮 ２ 甲基胺基）苯甲酸］及其酯型β Ｄ 葡糖苷酸结合物可获得分子结构的丰富信息     

3H－1，2－二氢－2－（4－甲基苯胺基）甲基－1－吡咯里嗪酮在家兔体内主要代谢产物的研究

用高效液相色谱法对家兔单剂量ｉｇ７５０ｍｇ新抗炎镇痛剂３Ｈ－１，２二氢－２－（４－甲基苯胺基）－甲基－１－吡咯里嗪酮（Ｚ－４７）后尿中的代谢物进行了分离、检测。根据代谢物的色谱行为及与Ｚ－４７结构有关的其它药物的代谢途径，推测Ｚ－４７羧基衍生物［４－（３Ｈ－１，２－二氢－１－吡咯里嗪酮－２－甲基胺基）苯甲酸］是一可能的代谢产物，遂用化学方法合成了该衍生物。利用色谱保留值、紫外双波长吸收比值等对代谢物和标准品进行比较，并对尿样的酶水解产物进行色谱分析，证实Ｚ－４７羧基衍生物及其酯型β－Ｄ－葡糖苷酸结合物是Ｚ－４７在家兔体内的主要代谢产物。     

小克银汉霉菌对SFZ—47的代谢转化

利用微生物转化的方法，选取小克银汉霉为转化菌株，对新型抗炎镇痛剂ＳＦＺ－４７代谢物的种类与产率了研究，高效液相色谱法测试结果表明，该菌株对ＳＦＺ－４７能产生的率产物，且重现性好，单因素改变实验显示，菌株对发酵转化初始ｐＨ值极为敏感。正交试验结果发现，在３种较佳的转化条件下共获得１０种代谢物，在其中一种条件下，同时可得７种代谢物，在另一条件下，一主要代谢物的产率高达４１．６％，转化液为残留的母体药物     

高效液相色谱法测定家兔血浆中Z－47浓度及其在药代动力学研究中的应用

本文建立了测定家兔血浆中Ｚ－４７（３Ｈ－１，２－二氢－２－（４－甲基苯胺基）甲基－１－吡咯里嗪酮）的高效液相色谱法。选用μ－ＢｏｎｄａｐａｋＣ１８色谱柱，流动相为甲醇－磷酸二氢铵缓冲液（ｐＨ＝４）（３：２，Ｖ／Ｖ）。以安定为内标物。血浆样品先经碱化，用乙醚－正己烷（１：１，Ｖ／Ｖ）提取，分离有机相，再以１０％磷酸萃取，水相２０μＬ进样，紫外检测波长２９０ｎｍ。本法专属性强，精密度、准确性符合有关要求，操作简便。对６只家兔口服给药后应用本法成功地进行了初步的药代动力学研究。     

新型抗炎镇痛剂SFZ-47在家兔体内羟基化及其结合型代谢产物的鉴定

目的：鉴定新型抗炎镇痛剂SFZ-47［3H-1,2-二氢-2-(4-甲基苯胺基)甲基-1-吡咯里嗪酮］在家兔体内的羟基化及其结合型代谢产物。方法：选择4只健康家兔单剂量口服100 mg SFZ-47,收集0～10 h的尿样。将未经或经过β-D-葡萄糖苷酸酶/硫酸酯酶水解的尿样以Sep-Pak C₁₈固相萃取柱纯化后,采用LC/MSn方法对尿中推测的代谢物分别进行选择离子监测(SIM)和多级全扫描质谱(MSⁿ)分析。结果：在尿中首次检测到SFZ-47羟基化及其β-D-葡糖苷酸与硫酸结合型代谢物。结论：SFZ-47在家兔体内主要代谢途径应为苯环上的甲基先氧化成羟甲基和羧基,再分别与β-D-葡糖醛酸或硫酸结合。     

家兔尿中SFZ-47及其两种主要代谢产物的HPLC定量方法

建立了家兔尿中ＳＦＺ－４７及其两种主要代谢产物ＳＦＺ－４７羧基衍生物（Ｍ１）及该衍生物的酯型β－Ｄ－葡糖苷酸（Ｍ２）的 ＨＰＬＣ测定方法，并用该法对单剂量口服２３０ｍｇ ＳＦＺ－４７的 ３只家兔尿样进行了定量分析．结果表明：在０～２４ｈ内，ＳＦＺ－４７，ＭＩ和Ｍ２的累积排泄量分别占给药剂量的（８．３±０．４８）％，（１８．９３±２．６６）％和（２３．４２±８．００）％．     

新抗炎镇痛剂SFZ-47在家兔体内主要代谢产物的分离与鉴定

目的建立家兔尿液中新抗炎镇痛剂SFZ-47一葡糖苷酸代谢物的分离纯化方法,并对其结构进行确证。方法健康家兔,单剂量ig SFZ-47 200 mg,收集0～24 h尿样;将尿样经冷冻干燥和甲醇溶解后,用半制备型HPLC对粗提物中该代谢产物进行分离与制备,以ESI-MSⁿ和¹HNMR技术对其进行结构确证。结果首次直接证明该代谢物为SFZ-47羧基衍生物的葡糖苷酸结合物。结论本法操作简便,分离效果好,可用于SFZ-47及其结构类似物葡糖苷酸结合物的分离与鉴定。     

3H-1,2-二氢-2-(4-甲基苯胺基)甲基-1-吡咯里嗪酮在家兔体内主要代谢产物的研究

用高效液相色谱法对家兔单剂量ig750mg新抗炎镇痛剂3H-1,2二氢-2-(4-甲基苯胺基)-甲基-1-吡咯里嗪酮(Z-47)后尿中的代谢物进行了分离、检测。根据代谢物的色谱行为及与Z-47结构有关的其它药物的代谢途径,推测Z-47羧基衍生物[4-(3H-1,2-二氢-1-吡咯里嗪酮-2-甲基胺基)苯甲酸]是一可能的代谢产物,遂用化学方法合成了该衍生物。利用色谱保留值、紫外双波长吸收比值等对代谢物和标准品进行比较,并对尿样的酶水解产物进行色谱分析,证实Z-47羧基衍生物及其酯型β-D-葡糖苷酸结合物是Z-47在家兔体内的主要代谢产物。     

2—苄氧基—及2—（2—苯基乙氧基）—5—氟—4（3H）—嘧啶酮的合成

自安本三治等报道,2-苄氧基-5-氟-4(3H)-嘧啶酮(1)具有抗肿瘤活性后,Baba等即以1为中间体,又合成了一系列糖苷类化合物,它们均具有抗肿瘤活性。因此我们进行了1及其同系物的合成研究。文献报道,1可由3在封管中与NaH和Ph CH_2OH反应而得,收率78.2％。     

HCMV蛋白酶抑制剂的研究(Ⅱ)杂环类抑制剂的设计与合成

目的 人巨细胞病毒（HCMV）是一种普遍存在的机会病原体。HCMV蛋白酶在装配蛋白产生和病毒壳体成熟中具有重要作用，抑制基作用可产生抗疱疹病毒药物。对杂环类HCMV蛋白酶抑制剂进行研究。方法 根据HCMV蛋白酶和拟肽类抑制剂复合物的晶体结构数据，借助计算机辅助药物设计手段，运用Docking(分子对接）技术，从MDDR库中筛选挑出35个预计可能与HCMV蛋白酶相互较好结合的杂环化合物。首先选择目标物2-（香豆素-3-基）-5-氟-4H-3,1-苯并恶嗪-4-酮（I）和3-（2-羟基-4-甲基-苯甲酰基）-2-（4-甲氧基-苯基）-2，3-二氢-异吲哚-1-酮（Ⅱ）为合成和检验对象。结果 设计并完成了目标物I和Ⅱ的合成路线。结论 所得产物的结构经MS，IR，^1H-NMR及元素分析确证与目标物I和Ⅱ相符。     

黑曲霉Aspergillus niger对人参皂苷Re的微生物转化

目的：筛选长白山人参土壤中的活性微生物,转化单体人参皂苷产生稀有人参皂苷成份。方法：从长白山人参根际土壤中分离各类菌株,对单体人参皂苷Re进行微生物转化,通过硅胶柱层析等方法对转化产物进行分离纯化,采用波谱解析及理化常数对其进行结构鉴定。结果：从长白山人参根际土壤中分离各类真菌菌株68株,3株真菌对三醇组人参皂苷Re具有转化作用,其中黑曲霉Aspergillusniger的转化活性较强,转化产物为人参皂苷Rg1、Rg2和Rh1。结论：首次报道黑曲霉能将人参皂苷Re转化为人参皂苷Rg1、Rg2和Rh1这一转化过程。     

Effect on metabolic enzymes and thyroid receptors induced by BDE-47 by activation the pregnane X receptor in HepG2, a human hepatoma cell line

2,2′,4,4′-Tetra-bromodiphenyl ether (BDE-47), an important congener among polybrominated diphenyl ether (PBDE) compounds, has been predominantly in environmental samples and human tissue. Thyroid disruption is the most sensitive endpoint effect among a number of health effects of exposure to BDE-47 in animals and humans. However, the detailed underlying mechanisms in humans are not well understood. In the present study, human pregnane X receptor (hPXR)-overexpressing HepG2 cell model and a dual-luciferase reporter assay system were constructed to investigate the role of hPXR in BDE-47–induced alterations of expression of metabolic enzymes and TR in vitro. The results showed that hPXR was significantly activated by BDE-47, and expression levels of both mRNA and protein of the thyroid receptor (TR) isoforms TRα1 and TRβ1 were decreased in hPXR-overexpressing HepG2 cells after BDE-47 treatment. However, the increased expression of hepatic microsomal phase I enzyme CYP3A4 and phase II enzymes, UGT1A3 and SULT2A1 were also found. Taken together, the results indicated that BDE-47 was a strong hPXR activator, activation of hPXR played an important role in BDE-47–induced down-regulation of TR, and up-regulations of CYP3A4, UGT1A3, and SULT2A1 participated in the process, which may provide more toxicological evidence on mechanisms of disruption of thyroid hormone induced by BDE-47.     

Synthesis and anticancer evaluation of N-benzoyl-N'-phenyltiourea derivatives against human breast cancer cells (T47D)

New anti-breast cancer compounds have been found and may prove to have stronger activity. To predict the activities of N-benzoyl-N'-phenylthiourea (BPTU) derivatives, namely N-(3-chloro)benzoyl-N'-phenylthiourea (3-Cl-BPTU) and N-(3,4-dichloro)benzoyl-N'-phenylthiourea (3,4-2Cl-BPTU) with Sirtuin-1 receptor (PDB code: 4I5I), molecular docking was conducted at the beginning of this study. The compounds were then synthesized from benzoyl chloride derivatives and N-phenylthiourea. Molecular structure was confirmed using FTIR, ¹H NMR, ¹³C NMR and Mass Spectra, while the anticancer activity was tested in vitro against human breast cancer cells (T47D) using MTT assay. The results indicated that the anti-cancer activities of the test compounds were better than those of the hydroxyurea as the reference compound, evidenced by the Rerank Score (RS). Furthermore, cytotoxic effect of 3-Cl-BPTU (IC₅₀: 0.43 mM) and 3,4-dichloro-BPTU (IC₅₀: 0.85 mM) showed better result compared with hydroxyurea (IC₅₀: 4.58 mM). Therefore, we concluded that these compounds could possess termendous potential as the candidate for a new anticancer drug.     

2,6-二甲基-4-(3-硝基苯基)-1,4-二氢-3,5-吡啶二羧酸-3-甲酯-5-戊酯对兔小肠缺血再灌注损伤所致休克的保护作用

探讨二氢吡啶类钙通道阻滞剂２，６－二甲基－４－（３－硝基苯基）－１，４－二氢－３，５－吡啶二羧酸－３－甲酯－５－戊酯（ＭＮ９２０２）对小肠缺血再灌注损伤所致休克的保护作用．家兔用无创伤动脉夹夹闭肠系膜上动脉６０ｍｉｎ后松夹，复制小肠缺血再灌注模型．在肠缺血４５ｍｉｎ后ｉｖＭＮ９２０２１μｇ·ｋｇ－１能部分提高血压水平，延缓左室内压和±ｄｐ／ｄｔｍａｘ的降低，减少肌酸激酶和乳酸脱氢酶的释放，使家兔存活时间明显延长（１４２±５０ｍｉｎｖｓ９２±４８ｍｉｎ，Ｐ＜０．０５），２ｈ存活率明显提高（７／１０ｖｓ２／１０，Ｐ＜０．０５）．结果表明ＭＮ９２０２能减轻小肠缺血再灌注引起的休克，改善心脏功能可能是药物的保护作用之一．     

Urinary tract infection in geriatric patients

Elderly patients with urinary tract infection (UTI) are believed less likely to be cured by antimicrobial therapy than younger patients. The reasons for this poorer outcome have not yet been clarified. We have investigated the effect of antimicrobial therapy in elderly patients with complicated UTI. Four-hundred and eighty patients, 244 men and 236 women, who had complicated UTI (266 symptomatic and 236 asymptomatic) and were 20–79 years of age, were treated with one of three different drugs; one was a newer quinolone and two were oral cephems. Multivariate logistic regression analysis of treatment outcome revealed that the clinical response was significantly related to general underlying diseases and diseases of the urinary tract, but not to age, symptomatic or asymptomatic UTI, or infection site such as the kidney or bladder. We concluded that the clinical effectiveness of an antimicrobial agent was not directly related to age, and that urological examination for underlying diseases and control of them is quite important for effective treatment and control of complicated UTIs, especially in elderly patients.     

马蓝的化学成分研究

Seven compounds have been isolated from the whole plant of Strobilanthes cusia (Nees) O. Ktze. Three of them are triterpenes (Ⅰ～Ⅲ), two are indole alkaloids (Ⅳ, Ⅴ), two are quinazolinone alkaloids (Ⅵ, Ⅶ). On the basis of spectral analysis and physicochemical properties, their structures were established as lupeol (Ⅰ), betulin (Ⅱ), lupenone (Ⅲ), indigo (Ⅳ), indirubin (Ⅴ), 4 (3H)-quinazolinone (Ⅵ), 2, 4 (1H, 3H)-quinazolinedione (Ⅶ). Ⅵ and Ⅶ were found from natural plant for the first time.The results of the pharmacological tests demonstrate that compound Ⅴ has anticancer activity and compound Ⅵ has hypotensive action. Compound Ⅶ can be quantitatively determined by HPLC, which may serve as a quality control standard for materia medica and its preparations. Compounds Ⅵ and Ⅶ have been confirmed by means of synthesis.