棕榈酰-苯丙氨酸甲酯凝胶因子的制备及其性质考察

目的合成一种自组装超分子有机凝胶因子——棕榈酰-苯丙氨酸甲酯（C16-L-Phe-OMe）,并对其进行结构表征和性质考察。方法以L-苯丙氨酸甲酯盐酸盐为母核、棕榈酰氯为酰化剂,合成棕榈酰-苯丙氨酸甲酯凝胶因子,采用IR、^1H-NMR、MS等手段对其结构进行表征,并考察其熔点、在各种植物油中的最低胶凝浓度、相转变温度等凝胶行为。结果IR、^1H-NMR、MS等分析结果表明合成物质的结构为棕榈酰-苯丙氨酸甲酯,产率为73.40%,熔程为71.5～72.3℃,室温下在橄榄油、一级大豆油、葵花油、大豆油、花生油中的最低胶凝浓度分别为150、160、160、170、190g·L^-1,相转变温度随凝胶因子浓度的增加而升高。结论 C16-L-Phe-OMe的制备工艺简单,在橄榄油、一级大豆油、葵花油中具有很强的胶凝能力,是一种优良的有机凝胶因子,适于作为药物控释载体。     

脂酰苯丙氨酸甲酯同系凝胶因子的合成及凝胶性质考察

目的合成一系列脂酰苯丙氨酸凝胶因子——肉豆蔻酰-苯丙氨酸甲酯(C14-L-Phe-OMe)、棕榈酰-苯丙氨酸甲酯(C16-L-Phe-OMe)及硬脂酰-苯丙氨酸甲酯(C18-L-Phe-OMe),并对其进行结构表征和性质考察。方法以L-苯丙氨酸甲酯盐酸盐为母核,肉豆蔻酰氯、棕榈酰氯、硬脂酰氯为酰化剂,合成一系列脂酰苯丙氨酸凝胶因子,采用IR、1H-NMR、MS等手段对其结构进行表征,并考察其熔点、一级大豆油中的相转变温度和凝胶能力。结果成功合成了C14-L-Phe-OMe、C16-L-Phe-OMe及C18-L-Phe-OMe,并确证了其结构;三种凝胶因子的熔程分别为61.3~63.1、72.1~73.0和62.3~64.1;胶凝能力大小顺序是:C16-L-Phe-OMe>C18-L-Phe-OMe>C14-L-Phe-OMe;三种凝胶因子在一级大豆油中的胶凝焓变分别为42.58 k J/mol、22.61 k J/mol和65.01 k J/mol。结论合成的一系列脂酰苯丙氨酸凝胶因子具有较好的胶凝能力,其中C16-L-Phe-OMe的胶凝能力最强,有望作为一种局部给药的长效释药载体。     

注射用琥珀酰明胶的制备

目的制备注射用琥珀酰明胶,以提高其稳定性及运输贮藏的便易性。方法合成琥珀酰明胶,并用IR、1H-NMR及UV光谱方法对其进行表征,采用喷雾干燥和冷冻干燥工艺制备注射用琥珀酰明胶,同时对所制备产品的再分散性质进行了初步考察。结果合成条件为:明胶质量浓度为200 mg.L-1,琥珀酸酐质量浓度为10 mg.L-1,pH值为10,温度90℃,时间2 h。冷冻干燥法制备的注射用琥珀酰明胶与琥珀酰明胶对照品的1H-NMR、IR及UV谱图均相符。以质量浓度50 mg.L-1的甘露醇为冻干保护剂制备的产品外观蓬松饱满,复溶时间短。配成输液后渗透压为288 mmol.L-1,pH值为7.19。结论运用丁二酰化法合成琥珀酰明胶,以质量浓度50 mg.L-1甘露醇为冻干保护剂,利用冷冻干燥法可相对较稳定地制备拥有较好外观及溶解度的注射用琥珀酰明胶,且配制成输液后渗透压及pH值符合静脉用药要求。     

盐酸文拉法辛温敏型原位凝胶的研制

目的确定盐酸文拉法辛温敏型原位凝胶的基质处方。方法以不同质量浓度泊洛沙姆作为温敏材料,用卡波姆、聚乙烯吡咯烷酮、羟丙基甲基纤维素作黏膜黏附剂,考察凝胶的相变温度和黏附力,优选基质处方。结果确定180g·L-1泊洛沙姆407和3.0g·L-1聚乙烯吡咯烷酮组合作为盐酸文拉法辛温敏型原位凝胶的处方基质,其胶凝温度为31.7℃,黏附力98.1g·cm-2。结论选定的基质处方可用于制备盐酸文拉法辛温敏型原位凝胶。     

喷昔洛韦眼用温度敏感原位凝胶的制备及质量控制

目的 制备喷昔洛韦(penciclovir,PCV)温度敏感原位凝胶,对其进行了处方优化筛选,并建立其质量控制方法.方法 考察含有不同泊洛沙姆407(Pluronic F127)和泊洛沙姆188(Pluronic F68)浓度配比的处方对原位凝胶胶凝温度、流变学性质、质构特性和体外药物释放行为等的影响,从而设计和优化处方.结果 得到最佳凝胶基质组成为19%F127/0.3%F68,其胶凝温度33.7℃;达到34℃时粘度和胶凝强度明显增大;PCV自凝胶中的释放具有一定的缓释效果.结论 喷昔洛韦眼用温度敏感原位凝胶有望开发成为一种新型眼部给药制剂.     

可注射更昔洛韦温敏型原位凝胶剂的研究

构建温敏型三嵌段共聚物,研究其理化性质以及用其制备的可注射更昔洛韦温敏型原位凝胶剂的制剂特性。以聚乙二醇（PEG）作为亲水嵌段．丙交酯（LA）和β-丁内酯（β-BL）的无规共聚物PBLA作为疏水嵌段．采用开环聚合法合成温敏型三嵌段共聚物PBLA-PEG-PBLA,并对其理化性质进行表征,考察其溶液的胶凝温度／临界凝胶浓度、流变学性质、通针性和溶蚀行为以及以更昔洛韦作为模型药物、用其制得的可注射载药温敏型原位凝胶剂的体外释放特性。合成的PBLA-PEG-PBLA嵌段共聚物重均分子质量在6000左右,多分散系数为1．5左右;其溶液临界凝胶浓度（g·mL^-1）为5％-10％,质量浓度（g·mL^-1）在10％～25％时胶凝温度为31～35℃,接近并略低于体温：其凝胶在低温下储能模量与黏度较小,当温度接近相转变温度后两者迅速增大：其载药凝胶剂累计释放量经拟合显示遵循一级动力学方程,并呈扩散释药机制。较低质量浓度[10％15％（g·mL^-1）的PBLA—PEG—PBLA更符合玻璃体注射要求,更适用于制备可注射载药温敏型原位凝胶剂。     

高效液相色谱法测定L-缬氨酸甲酯盐酸盐中L-异亮氨酸甲酯盐酸盐

目的:采用衍生化为辅助手段,建立高效液相色谱法测定缬沙坦起始物料L-缬氨酸甲酯盐酸盐中杂质L-异亮氨酸甲酯盐酸盐含量的方法。方法:采用岛津VP-ODS C18色谱柱(150 mm×4.6 mm,5μm);以乙酸钠缓冲液(pH 7.2)-甲醇-乙腈(20∶45∶30)为流动相,流速为1.0 mL.min-1;检测波长为262 nm;柱温为40℃。采用9-芴基甲酰氯为衍生化试剂,考察衍生化试剂浓度,反应静置时间,超声时间等衍生化条件,确定衍生化的方法并进行方法学验证。结果:衍生化反应条件为:衍生化试剂浓度10 mg.mL-1,反应静置时间20 min,超声10 s。经方法学验证,L-异亮氨酸甲酯盐酸盐在15～75μg.mL-1范围内线性良好,其平均回收率为92.943%,RSD为4.965%,溶液在5 h内稳定性。结论:该方法简便、快速、耐受性好,符合有关物质方法学验证要求,可用于杂质L-异亮氨酸甲酯盐酸盐的含量测定。     

LC-MS/MS法测定2-脱氧-D-核糖中的甲磺酸甲酯和甲磺酸乙酯的含量

目的建立LC-MS/MS法检测2-脱氧-D-核糖中基因毒性杂质甲磺酸甲酯和甲磺酸乙酯的方法。方法选用C18色谱柱(以十八烷基硅烷键合硅胶为填充剂,250 mm×4.6 mm,5μm),以甲醇-水(体积比30∶70)为流动相,流速为1.0 m L·min-1,分流比为30%,柱温为40℃,进样量为10μL。采用APCI离子源检测扫描方式负离子模式检测。结果甲磺酸甲酯和甲磺酸乙酯质量浓度在20~200μg·L-1内与峰面积线性关系良好,甲磺酸甲酯和甲磺酸乙酯的检测限为4μg·L-1,定量限为10μg·L-1,甲磺酸甲酯和甲磺酸乙酯的回收率分别为104.8%(RSD=7.93%,n=9)和101.0%(RSD=5.97%,n=9)。结论本方法灵敏、专属性强,适用于2-脱氧-D-核糖中基因毒性杂质甲磺酸甲酯和甲磺酸乙酯的检测。     

抗氧剂L-半胱氨酸盐酸盐在水溶液中的氧化反应速率常数

目的 测定抗氧剂L-半胱氨酸盐酸盐在水溶液中与氧反应的速率常数,并评价其抗氧化能力.方法 在25℃、35℃、45℃下,向反应液中持续通入空气以维持溶解氧浓度恒定,并用氧电极测定其浓度;用碘量法测定L-半胱氨酸盐酸盐在水溶液中不同时刻的浓度,做出降解曲线,计算各温度下的氧化降解速率常数.结果 25℃时,L-半胱氨酸盐酸盐在pH4.0、pH6.8缓冲溶液中与氧的反应均为表观零级反应,而在pH9.0缓冲溶液中为表观一级反应.3个不同pH条件下的表观反应速率常数分别为7.78、30.1μmol·L-1·h-1、5.03×10-2 h-1.结论 L-半胱氨酸盐酸盐在弱酸性条件下,反应速率较慢,抗氧化能力较弱;在中性和弱碱性条件下反应速率较快,抗氧化能力较强.     

氯霉素温敏型眼用原位凝胶的研制

目的制备氯霉素泊洛沙姆眼用原位温敏型凝胶并建立其质量控制方法。方法以泊洛沙姆P407和P188为温敏材料,通过测定溶液-凝胶相转变温度优化处方;采用紫外分光光度法测定氯霉素含量。结果氯霉素温敏型原位凝胶的胶凝温度随P407浓度增大而降低,随P188浓度增加先升高后降低,模拟泪液的稀释可使胶凝温度升高,建立了泪液稀释后相变温度与泊洛沙姆浓度的拟合方程,经Design-Expert软件优化出的氯霉素温敏型原位凝胶最佳处方为25%P407和4.19%P188;优化处方在29.5℃时为自由流动的液体,泪液稀释后在34.6℃能够发生相变形成凝胶。结论该眼用温敏凝胶符合眼部应用要求,体现出良好的应用前景。     

Ethyl acrylate-induced gastric toxicity. II. Structure-toxicity relationships and mechanism

Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).     

Synthesis and antimicrobial activity of hydroxy-isophthalaldehyde acid derivatives

4-hydroxy-isophthalaldehyde acid (1), its alkyl esters (methyl, ethyl, propyl and butyl) and alkyl ethers (propyl, butyl, pentyl and esyl), as well as 6-hydroxy-isophthalaldehyde acid (2) ita alkyl esters (methyl and ethyl), 4-hydroxy-5-iodo-isophthalaldehyde acid (3) and its methyl ester were synthesized and characterized. Antimicrobial and antifungal activity was tested and the LD50 of the most active compound 4 was determined.     

L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.     

Ochratoxins in Wines: A Review of Their Occurrence in the Last Decade,Toxicity, and Exposure Risk in Humans

Ochratoxins (OTs) are mycotoxins frequently found in wines, and their contamination can occur during any stage of the winemaking process. Ochratoxin A (OTA) has been the most widely reported and the only one whose concentrations are legislated in this beverage. However, ochratoxin B, ochratoxin A methyl ester, ochratoxin B methyl ester, ochratoxin A ethyl ester, ochratoxin B ethyl ester, ochratoxin α, ochratoxin β, OTα methyl ester, OTA ethyl amide, and OTA glucose ester have also been reported in wines. Thus, detecting only OTA would lead to the underestimation of ochratoxin levels, which is a risk to human health. Considering the threat represented by the presence of ochratoxins in wines and the long-term health problems that they can cause in wine drinkers, this paper aims to review reports of the last 10 years regarding the presence of different ochratoxins in wines and how the winemaking process influences the degree of contamination, mainly by OTA. Additionally, toxicity from human exposure due to the consumption of contaminated wines is addressed.     

Reactivity of 7-dithiocarboxy-imidazo[2,1-b]thiazoliumbetaine with aliphatic alkylating agents

We have reported earlier on the reactivity of 7-dithiocarboxy-3-phenyl-5,6-dihydro imidazo[2,1-b]thiazolium-betaine with severalpara-substituted phenacyl bromides. In this work reactions of 7-dithiocarboxy-3-phenyl(or methyl)-5,6-dihydro imidazo[2,1-b]thiazolium-betaine with a series of aliphatic alkylating agents of α-halo ketone, γ-halo keto ester and α-halo ester were examined for the similar purpose. In case of α-halo ketone or γ-halo keto ester such as α-chloro acetone or ethyl 4-chloro acetoacetate new biheterocyclic compound was obtained via ring transformation reaction. However, reaction of the betaine with methyl(or ethyl) bromoacetate used as a α-halo ester, gave, instead, S-alkylated quarternary ammonium salt.     

Differential pharmacological effects of beta-carboline-3-carboxylic acid esters

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid have been studied in vitro and in vivo. All three esters were found to be potent inhibitors of 3H-flunitrazepam binding in the rat cerebellum and cerebral cortex in vitro. In vivo, the methyl and ethyl esters were potent proconvulsant agents, whereas the propyl ester was not. Furthermore, the methyl ester produced convulsions which were blocked by the ethyl and propyl esters as well as by diazepam. These in vivo differences may be due to the beta-carboline esters having different proportions of agonistic and antagonistic actions at their recognition sites.     

Design, synthesis, and calcium channel antagonist activity of new 1,4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent

A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea pig ileal longitudinal smooth muscle. The results for the symmetrical ester series showed that increasing the length of the chain in C3- and C5-ester substituents increased the activity and the most active compound was the diphenylethyl ester derivative, so it was more active than the reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increasing lipophilic properties in the R substituent, increased the activity. The most active compounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active than nifedipine.     

牛蒡根乙酸乙酯部位的化学成分研究

摘 要 目的：研究牛蒡根乙酸乙酯部位的化学成分。方法: 采用柱色谱和制备液相等方法对牛蒡根乙酸乙酯部位化学成分进行分离纯化,运用波谱学方法鉴定化合物结构。结果: 从牛蒡根乙酸乙酯部位共分离得到了7个化合物,分别鉴定为: 邻苯二甲酸二丁酯（1）、咖啡酸甲酯（2）、8- 甲氧羰甲基-对羟基肉桂酸（3）、3-O-咖啡酰奎宁酸甲酯（4）、咖啡酸（5）、3,4-O-双咖啡酰奎宁酸甲酯（6-a）和3,5-O-双咖啡酰奎宁酸甲酯（6-b）、乙二醇（7）。结论:确定其中8- 甲氧羰甲基-对羟基肉桂酸（3）为首次从菊科植物中分离获得;3-O-咖啡酰奎宁酸甲酯（4）、3,4-O-双咖啡酰奎宁酸甲酯（6-a）和3,5-O-双咖啡酰奎宁酸甲酯（6-b）为首次从牛蒡属植物中分离得到。     

Studies on hydrolytic and oxidative metabolic pathways of anhydroecgonine methyl ester (methylecgonidine) using microsomal preparations from rat organs

During smoking of cocaine-base (crack), anhydroecgonine methyl ester (AEME, methylecgonidine) is formed in large amounts as a pyrolysis product of cocaine and is absorbed in the lungs. The metabolism of AEME was studied in the present investigation using microsome preparations from rat liver, lung, kidney, and brain. Potential metabolites of AEME were synthesized and used as substrate to complement the experiments. Analysis of the incubation mixtures was performed using gas chromatography-mass spectrometry and nanoelectrospray multiple-stage mass spectrometry. Screening for metabolites was focused on postulated oxidative pathways, chemical and enzymatic hydrolysis, and ethanol dependent transesterification as known from cocaine metabolism. Enzymatic hydrolysis of AEME to anhydroecgonine (AE), which was inhibited by sodium fluoride, was found in all microsomal preparations. Liver microsomes exhibited the highest activity, brain microsomes the lowest. Anhydronorecgonine methyl ester (ANEME) and anhydroecgonine methyl ester N-oxide were identified as AEME metabolites of liver and lung microsomes only. In the presence of ethanol AEME was metabolized to anhydroecgonine ethyl ester and anhydronorecgonine ethyl ester. Further metabolism of AE or ANEME was not observed. No N-hydroxy-anhydronorecgonine derivatives were found which could represent precursors of cytotoxic metabolites as known to be formed from cocaine.     

Synthesis and calcium channel antagonist activity of 1,4-dihydropyridine derivatives containing 4-nitroimidazolyl substituents

Alkyl, cycloalkyl and arylakyl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitro phenyl group at position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units (n > 1) decreases activity. In the phenylalkyl ester series increasing the length of methylene chain increases activity. In the series of unsymmetrical phenylalkyl esters (R2 = Me or Et) increasing the length of the methylene chain decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. Among symmetrical diesters (methyl, ethyl and phenylpropyl derivatives) and among unsymmetrical series (benzyl methyl, benzyl ethyl and phenethyl ethyl derivatives) were more active than the reference drug nifedipine. The unsymmetrical phenethyl ethyl derivative was the most potent antagonist tested. The structure-activity data indicate that the 4-(1-methyl-4-nitro-5-imidazolyl) moiety, bioisoester of 2-nitro-phenyl moiety, is as good as other nitro-imidazolyl moieties.