醋酸兰瑞肽(lanreotide acetate)

醋酸兰瑞肽(lanreotide acetate)于2007年8月30日由美国FDA批准上市,该药由IPSEN公司开发研制,商品名为索马杜林(Somatuline De-pot)。本品为注射剂,用于肢端肥大症的长期治疗[1],适用于对于手术和(或)放射疗法不应答的患者,或者不适合进行手术和(或)放射疗法治疗的患者。兰瑞肽中文化学名称:3-(2-萘基)-D-丙氨酰基-L-半胱氨酰基-L-酪氨酰基-D-色氨酰基-L-赖氨酰基-L-缬氨酰基-L-半胱氨酰基-L-苏氨酰胺,环(2~7)二硫化物;英文化学名称:3-(2-naphthalenyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteiny…     

UPLC/MS比较分析达托霉素和内酯水解物的酸降解产物

摘要：达托霉素是一种正在临床使用的新型抗耐药菌抗生素。但是由于其结构特点，达托霉素容易受酸碱影响产生降解。 本文利用UPLC/MS比较分析了达托霉素及其内酯水解物酸降解后的产物，发现达托霉素主要的降解产物为天冬氨酰-丙氨酰内 酰胺键断裂产物，内酯水解物酸的主要降解产物为分子量974的七肽和分子量1160的九肽。通过比较，确定分子量974的有关物 质主要来源于内酯水解物的酸降解。并且通过核磁共振检测，确定了该七肽物质的化学结构和氨基酸连接顺序。     

利用产黄青霉和产黄小枝顶孢环化酶合成青霉素G

δ(L-α-氨基己二酰基)-L-半胱氨酰基-D-缬氨酸(ACV)的三肽结构是青霉素、头孢菌素和头霉素生物合成途径中的一种中间产物(图1)。它似乎是由三种氨基酸即α-氨基乙二酸、半胱氨酸和缬氨酸组成的一种非核蛋白体的缩合作用生成的。上述三种组份氨基酸再通过异青霉素 N 合成酶(即所谓环化酶)被环化成异青霉素 N。这种具有抗菌活力的化合物(异青霉素 N)的酶法合成的成功促使对几种与 ACV 有类似结构的肽之环化作用进行更广泛深入的研究,以期获得结构有所改良、抗菌谱有所改进的某些青霉素。     

合欢皮中一个新的三萜皂甙

从合欢皮的乙醇提取物中用色谱法分离得到1个三糖链三萜皂甙（1）,其21位侧链含有较为少见的木糖。经化学和波谱分析,将皂甙1的结构鉴定为3－O－[β-D-吡喃木糖基-(1→2)-β-D-吡喃呋糖基－（1→6)-β-D-吡喃葡萄糖基]-21-O-{(6S)-2-反式－2－羟甲基－6－甲基－6－O－[4-O-(6R)-2-反式－2,6－二甲基－6－O－β-D-吡喃木糖基）－2,7－辛二烯酰基]－β-D-吡喃鸡纳糖基]-2,7-辛二烯酰基}-金合欢酸－28－O－β－D－吡喃葡萄糖基－（1→3)-[α-L-呋喃阿拉伯糖基－（1→4)]-α-L-吡喃鼠李糖基－（1→2)-β-D-吡喃葡萄糖基酯,为一新化合物,命名为合欢皂甙J23（1）。     

翻白草中酚酸类化学成分的研究

目的 研究翻白草中的酚酸类化学成分.方法 采用硅胶、大孔树脂及聚酰胺柱色谱等手段,分离纯化翻白草中70％乙醇提取部位的酚酸类成分,并通过光谱法鉴定结构.结果 分离并鉴定了6个单体化合物,分别为3-甲基鞣花酸-4′-O-α-L-鼠李糖苷(Ⅰ)、3,3′,4-三甲基鞣花酸-4′-O-β-D-葡萄糖苷(Ⅱ)、3,3 ′-二甲基鞣花酸(Ⅲ)、没食子酸(Ⅳ)、委陵菜酸(Ⅴ)、山奈酚-3-O-β-D-6-O-(对羟基桂皮酰基)-吡喃葡萄糖苷(Ⅵ).结论 化合物Ⅱ、Ⅲ、Ⅴ、Ⅵ为首次从该植物中分离得到.     

藏药独一味根化学成分的研究

继前报从藏药独一味(Lamiophlomisrotatakudo)根的正丁醇提取物中分离得到两个甙类成分。经化学和光谱分析,两个化合物的结构分别鉴定为3-羟基-4-甲氧基苯乙基-O-[α-L-吡喃鼠李糖(1→3)]-O-[β-D-呋喃芹菜糖(1→6)]-4-O-阿魏酰基-β-D-吡喃葡萄糖甙(1)和3-甲氧基-4-羟基苯乙基-O-[α-L-吡喃鼠李糖(1→3)]-O-[β-D-呋喃芹菜糖(1→6)]-4-O-阿魏酰基-β-D-吡喃葡萄糖甙(2),后者为一新化合物,命名为独一味甙A(lamiophlomiosideA)。     

多黏菌素E类似物的纯化和结构鉴定

目的对硫酸多黏菌素中的低含量成分进行纯化和鉴定。方法利用两次反相色谱纯化制备得到单组份,并通过Nα-(2,4-二硝基-5-氟苯基)-L-丙氨酰胺(Nα-(2,4-Dinitro-5-fluorophenyl)-L-alaninamide,FDAA)试剂衍生法研究组分的组成氨基酸及其构型。基于二级质谱和氨基酸组成的结果对化合物进行了结构鉴定。结果多黏菌素E2的氨基酸组成、分子量与文献报道一致;杂质3和杂质9结构中含有L-Leu残基和羟基化的脂肪酸链;杂质6含有L-Val残基。结论杂质3、杂质6和杂质9分别为3-OHE2、Val-E2和3-OH-E1。     

中国沙棘果实的化学成分及其体外抗氧化活性研究

目的 研究中国沙棘果实的化学成分,并测定部分化学成分体外活性.方法 采用95%乙醇渗滤提得总浸膏,经溶剂萃取及柱层析分离,采用化学及光谱方法进行结构鉴定,并对小鼠视网膜色素上皮细胞(RPE)建立H2O2损伤模型,使用3种单体与细胞共孵育,进行MTT检测分析.结果 分得3个新化合物,分别鉴定为异鼠李素-3-O-β-D-(6-O-反式芥子酰基)槐二糖-7-O-α-L-鼠李糖苷(Ⅰ)、山柰素-3-O-β-D-(6-O-反式芥子酰基)槐二糖-7-O-α-L-鼠李糖苷(Ⅱ)和槲皮素-3-O-β-D-(6-O-反式芥子酰基)槐二糖-7-O-α-L-鼠李糖苷(Ⅲ).化合物Ⅲ对RPE有抗氧化活性,化合物Ⅰ则无,槲皮素活性最强.结论 研究结果可为中国沙棘的临床应用提供理论依据.     

从月桂树中分离到抗MRSA活性成分

本文发现一种对MRSA具有抗菌活性的月桂树叶提取物,纯化出了2种具有该活性的类黄酮物质并鉴定出它们分别是,山奈酚-3-O-α-L-（2″,4″-di-E-P-香豆酰基）-鼠李糖苷（C2）和山奈酚-3-O-α-L-（2″-E-P-香豆酰基．4″-Z-p-香豆酰基）一鼠李糖苷（C3）。     

那他霉素关键杂质的制备及其结构鉴定

目的 分离纯化那他霉素关键工艺杂质，并鉴定其结构，为那他霉素工艺和质量控制奠定基础。方法 采用色谱纯化技术，分离制备那他霉素粗品中的关键杂质，经LC-MS和NMR分析鉴定杂质结构。结果 建立了那他霉素工艺杂质的分离纯化方法，制备得到了3个杂质化合物，并通过波谱分析鉴定了化合物结构，其中杂质1为那他霉素的C2位差向异构体；杂质2为那他霉素的C18位甲氧基取代产物；杂质3为那他霉素三元氧环开环后脱去羟基形成的双键产物。结论 杂质化合物与那他霉素具有相似的骨架结构，均由那他霉素生产过程产生，为那他霉素原料药的生产工艺开发和质量控制提供了技术参考。     

达托霉素发酵过程中前体癸酸的添加策略研究

采用补料培养流加方式研究达托霉素发酵过程中前体物质癸酸的起始添加时间、添加量、癸酸耦合剂以及变速流加癸酸对发酵法生产达托霉素的影响。研究表明,达托霉素发酵过程中前体癸酸最佳起始添加时间为开始发酵后第36 h;癸酸最佳添加量为癸酸∶油酸甲酯(1∶1)70μL/12 h;癸酸最佳耦合剂为乙醇,配比为2.5∶1;变速添加癸酸溶液可使达托霉素的产量略有提高。     

Characterization and relative response factor determination of process related impurity in Naproxen by nuclear magnetic resonance spectroscopy

In the impurity profile of naproxen around 0.6% unknown polar impurity was detected by high performance liquid chromatography (HPLC). The product ion spectrum of the impurity and Naproxen was recorded in LCMS/MS and the fragmentation pattern of the impurity was observed to be similar to the fragmentation pattern of Naproxen with only a difference of two atomic mass units. The high resolution mass spectrum (HRMS) of the impurity displayed a protonated molecular ion at m/z 229.0863, which corresponds to the pseudomolecular formula C₁₄H₁₃O₃⁺. Based on LC/MS/MS, HRMS, 1D and 2D NMR data, the structure of the impurity was characterized as 2-(6-methoxynaphthalen-2-yl)acrylic acid. The acrylic acid impurity was synthesized in the laboratory and co injected in HPLC to confirm the retention time. RRF of the impurity was determined by ¹H NMR method and also by conventional HPLC slope method and the RRF values are found to be 6.11 and 5.64, respectively. The values are comparable and ¹H NMR method of RRF determination is complimentary and can be effectively used as an alternative method to conventional HPLC method especially in early stages of development when availability of impurity standards is not possible.     

加校正因子的主成分自身对照法测定布洛芬中杂质4-异丁基苯甲酸的含量

目的建立一种加校正因子的自身对照法测定布洛芬中已知杂质(4-异丁基苯甲酸)的方法。方法测定布洛芬和4-异丁基苯甲酸的线性方程,以斜率计算杂质4-异丁基苯甲酸相对于主成分布洛芬的校正因子;通过方法学考察,表明所采用的高效液相色谱法测定布洛芬中4-异丁基苯甲酸的含量可行;再采用外标法和加校正因子的主成分自身对照法分别测定三批布洛芬中4-异丁基苯甲酸的含量,并用统计学软件SPSS 13.0分析两组数据的差异。结果测得4-异丁基苯甲酸的校正因子为0.129,经方法学考察表明此方法准确可靠,且应用统计学软件分析本方法与外标法测得数据,结果表明两方法所测得数据无统计学差异。结论用加校正因子的主成分自身对照法测定布洛芬中4-异丁基苯甲酸的含量,方法准确可行。     

Identification of a new impurity in lisinopril

LC-UV scan of lisinopril revealed the presence of an unknown impurity (approximately 0.14%) at a relative retention time of 3.26 employing phosphate buffer-acetonitrile as binary gradient system while LC-MS analysis with binary gradient system comprising of a ammonia-ammonium acetate buffer (pH 5.0) and acetonitrile indicated it to be C31H41N3O7. The impurity was isolated by preparative HPLC utilizing a linear gradient of water and acetonitrile. The structural analysis of the isolated product by 1H, 13C NMR, mass spectroscopy and FT-IR revealed it to be a 4-phenyl butanoic acid derivative (CL) of lisinopril.     

Absorption Enhancement of Rectally Infused Cefoxitin Sodium by Medium-Chain Fatty Acids in Conscious Rats: Concentration–Effect Relationship

The objective of this study was to assess the relative absorption promoting potency in terms of concentration–effect relationships of the medium-chain fatty acids hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid in conscious rats, using cefoxitin sodium as the rectally delivered model compound. Rectal uptake of cefoxitin, which was absorbed to a limited extent without enhancer (30 ± 25%), proved to be significantly enhanced by 2.0 M sodium hexanoate, 0.69 M sodium octanoate, and 0.22 M sodium decanoate, resulting in mean bioavailabilities of 102 ± 24, 68 ± 25, and 68 ± 10%, respectively. Thus, increasing fatty acid chain length results in increased enhancing potency from hexanoic acid to decanoic acid. However, using dodecanoate a statistically significant effect could not be reached, because of its limited aqueous solubility. Optimal chain length for absorption enhancement by medium-chain fatty acids is probably determined by interplay of intrinsic effects on mucosal permeability and solubility of the medium-chain fatty acid.     

Identification of an Escherichia coli Protein Impurity in Preparations of a Recombinant Pharmaceutical

A host-cell protein impurity found in preparations of recombinant human acidic fibroblast growth factor (aFGF) was identified. Samples of aFGF examined by western blot analysis employing antiserum raised against an Escherichia coli cell lysate contained an immunoreactive protein with a molecular weight of approximately 26,000. The impurity was chromatographically isolated and the N-terminal sequence was determined. Comparing the sequence to a protein database provisionally identified the isolated impurity as the S3 ribosomal protein of E. coli. Monoclonal antibodies recognizing three separate epitopes of S3 confirmed the identity of the impurity in western blots of aFGF samples. The monoclonal antibodies were also used to estimate S3 levels in various preparations of aFGF.     

加校正因子的主成分自身对照法测定马来酸依那普利片有关物质

目的:建立加校正因子的主成分自身对照法测定马来酸依那普利片有关物质的含量.方法:用辛烷基硅烷键合硅胶为填充剂,以磷酸盐缓冲溶液(0.01 mol · L-1磷酸二氢钾溶液,用磷酸调pH值为2.2)-乙腈(75:25)为流动相;检测波长215 nm;柱温为50 ℃.测定依那普利拉(杂质Ⅰ)和依那普利双酮(杂质Ⅱ)相对于依...     

Alkamides from Cissampelos glaberrima

Two alkamides, deca-2E,4E-dienoic acid isobutylamide (1) and octa-2E,4E-dienoic acid isobutylamide (2), were isolated from the roots of Cissampelos glaberrima (Menispermaceae). Their structures were established by spectral and physical methods. Traces of two new alkamides, decen-2-oic acid isobutylamide (3) and decanoic acid isobutylamide (4), were identified by mass spectrometry.     

重组Arg34-GLP-1[7-37]杂质的分离纯化及质谱解析

目的:对重组Arg³⁴-胰高血糖素样肽-1(Arg³⁴-Glucagon-like Peptide-1[7-37],Arg³⁴-GLP-1[7-37])生产制备过程中的潜在杂质进行分离纯化和结构确证。方法:将发酵后的料液进行高效液相色谱分析检测,利用离子交换色谱和制备液相纯化得到Arg³⁴-GLP-1[7-37]纯品和杂质组分,使用纯品进行高温、酸碱等不同条件下的破坏实验,来探知杂质产生机理,利用MALDI-TOF质谱、蛋白质全序列测序等方式推断杂质的分子量与结构。结果:经阴离子交换色谱及反相制备纯化后,Arg³⁴-GLP-1[7-37]的纯度可达97.9%。分离出3种主要杂质并将其纯化至91.4%,99.2%和96.7%。基质辅助激光解吸电离飞行时间质谱(Matrix-assisted laser desorption/ionization time of flight mass spectrometry,MALDI-TOF)测试其[M+H]+分子量分别为1033.5446,2744.2397和3112.4475,通过破坏实验及Arg³⁴-GLP-1[7-37]的氨基酸序列来推测杂质1、杂质3与杂质9可能序列分别为E-F-I-A-W-L-V-R,H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W,H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-R。将纯化前后的成分进行比对,表明上述3个主要杂质是由发酵过程产生,通过极端条件处理这些杂质,其含量会显著增加。本研究解析的3个杂质结构及机理探究均为首次发表。结论:由于重组Arg³⁴-GLP-1[7-37]在高温、过酸过碱及氧化环境中不稳定,为防止纯化过程中主产物降解,应注意避免这些条件。本研究为胰高血糖素样肽-1(glucagon-like peptide1,GLP-1)及其类似物的研究指出了一些应避免的误区。     

Chemical profiling of the synthetic cannabinoid MDMB‐CHMICA: Identification,assessment, and stability study of synthesis‐related impurities in seized and synthesized samples

In this work, the most discriminating synthesis‐related impurities found in samples from seizures and controlled synthesis of the synthetic cannabinoid MDMB‐CHMICA (methyl (S)‐2‐(1‐(cyclohexylmethyl)‐1H‐indole‐3‐carboxamido)‐3,3‐dimethylbutanoate) were characterized. Based on 61 available powder samples of MDMB‐CHMICA, 15 key‐impurities were assessed, isolated in larger quantities via flash chromatography and structurally elucidated and characterized via high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Apart from verifying the relation of the impurities to the major component, the interpretation of their chemical structures with distinct structural elements provided first insights into the manufacturing process and the precursor compounds used. Following liquid chromatography mass spectrometry analysis of the 15 key‐impurities, the 61 seized samples of MDMB‐CHMICA were evaluated and classified via multivariate data analysis based on the corresponding relative peak areas. In a second part of this work, stability tests and multiple controlled syntheses of MDMB‐CHMICA were carried out to better understand variations in impurity signatures and to assess the significance of variations in the impurity patterns of seized samples. The last coupling step of the amino acid with 1‐(cyclohexylmethyl)‐1H‐indole‐3‐carboxylic acid was performed using the coupling agents oxalyl chloride, thionyl chloride, and HATU. Furthermore, the impact of reaction time and temperature on the impurity profile were investigated. Overall, eight new impurities were found in the controlled syntheses and two degradation products of MDMB‐CHIMCA were found in the course of the stability tests. Replicates of a synthesis conducted on the same day showed similar impurity signatures; on different days they showed discriminable signatures. The use of different coupling reagents or conditions gave clearly distinguishable impurity signatures.