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四苯基乙烯衍生物的合成与生物成像研究

中文摘要四苯基乙烯衍生物的合成与生物成像研究生物成像已成为当今生物研究中的有力工具，因为它提供了一种独特的方法来可视化细胞的形态细节。

荧光成像是实时，非侵入性监测生物分子的最强大的生物成像技术之一。

在过去几十年中，荧光探针的发展已促进细胞生物学的重大进展。

各种荧光探针，如半导体量子点，荧光碳点，Ln离子掺杂纳米材料，光致发光硅纳米颗粒，金属纳米团簇，有机小分子和有机荧光纳米颗粒已被合成并广泛研究用于生物应用。

聚集诱导发光（AIE）材料由于其优异的光学性质在生物成像领域得到了广泛的研究。

本论文基于四苯基乙烯（TPE），合成了一系列具有聚集诱导发光性质的荧光材料，并利用这些材料制备的纳米粒子进行生物成像。

具体研究内容如下：1.以四苯基乙烯为核，通过选择电子供体（D）和受体（A）的适当组合来设计和合成AIE红光分子。

通过将二甲胺和氰基部分引入TPE中，合成了具有不同AIE特性的四种新的红光化合物1,2,3和4。

四种化合物在固态下的最高量子产率可达到40％。

该化合物可以容易地制造成均一稳定的荧光纳米粒子。

并且化合物1负载的Pluronic F127 纳米粒子的发射主峰位在650nm处，并且高荧光量子产率为15.2％。

化合物1和2的纳米粒子对A549肺癌细胞的生物学成像表明这些化合物是癌细胞的有效荧光探针。

2.基于四苯基乙烯，合成出一种新型有机荧光染料TPE-2NH2。

这种材料发绿光，在NO存在下能与其发生反应生成的产物发红光，因此这种材料具有检测NO的性质。

由于材料的疏水性，我们将此染料负载到二氧化硅介孔纳米粒子中，制备了的纳米粒子均一，稳定，具有120nm的平均粒径，良好的生物相容性，较高的灵敏度。

将此纳米粒子与MCF-7细胞共培养，在细胞质中发现红光信号。

因此，此探针在细胞内检测到NO，表现出良好的应用价值。

关键词：聚集诱导发光，四苯基乙烯，生物成像1AbstractSynthesis and Bioimaging Application of TetraphenyletheneDerivativesBiological imaging (bioimaging) has become a powerful tool in biological research today because it offers a unique approach to visualize the morphological details of cells. Fluorescence imaging is one of the most powerful bioimaging techniques for real-time, non-invasive monitoring of biomolecules of interest in their native environments with high spatial and temporal resolution, and is instrumental for revealing fundamental insights into the production, localization, trafficking, and biological roles of biomolecules in complex living systems. The development of fluorescent probes has facilitated the recent significant advances in cell biology and medical diagnostic imaging. Over the past few decades, a variety of fluorescent probes, such as semiconductor quantum dots, fluorescent carbon dots, Ln ion doped nanomaterials, photo-luminescent silicon nanoparticles, metallic nanoclusters, organic small molecules and organic fluorescent nanoparticles have been synthesized and extensively investigated for biological applications. Aggregation Induce Emision (AIE) materials have been extensively studied in the field of biomimetic imaging due to their excellent optical properties. In this paper, based on tetraphenyl ethylene (TPE), a series of fluorescent materials with aggregation induced luminescent properties were synthesized and biologically imaged using the nanoparticles prepared by these materials. The specific research contents are as follows:1. Organic fluorescent probes play an important role in modernbiomedical research, such as biological sensing and imaging. However, the development of organic fluorophores with efficient aggregate state emissions expanded to the red to near-infrared region is still challenging. Here, we present a series of highly efficient Far Red/Near-Infrared (FR/NIR)2fluorescent compounds with aggregation-induced emission (AIE) properties by attaching electron donor and accepter to tetraphenylethene (TPE) moieties through a simple synthesis method. These compounds exhibit the pronounced fluorescence enhancement in aggregate state, the red to near infrared emission, and facile fabrication into uniform compouds-loaded Pluronic F127 NPs. The emission maximum of the NPs fabricated by the self assembly method is in the range of 550nm-850nm and the highest fluorescent quantum yield is 15.2%. The biological imaging of NPs of compound 1 and 2 for A549 lung cancer cell indicates that these compounds are effective fluorescent probes for cancer cell with high specificity, high photostability and good fluorescence contrast.2. Based on tetraphenylethylene, a novel organic fluorescent dye TPE-2NH2 was synthesized. This material is green emision, it can be reacted and the product generated red emision the presence of NO, so this material has the nature of the detection of NO. Due to the hydrophobicity of the material, we loaded the dye into the silica mesoporous nanoparticles. The prepared nanoparticles were homogeneous and stable, with an average particle size of 120 nm, good biocompatibility and high sensitivity. The nanoparticles were co-cultured with MCF-7 cells, and red light was found in the cytoplasm. Therefore, this probe in the cell to detect NO, showing a good application value.Keywords：Aggregation-induced emission，Tetraphenylethene，bioimaging3目录第1章前言 (1)1.1引言 (1)1.2具有AIE性质的化合物 (3)1.3AIE小分子生物探针的制备及其应用 (16)1.4负载AIE化合物的荧光纳米粒子的制备及其应用 (28)1.5本论文设计思想和主要内容 (32)1.6参考文献 (33)第2章具有AIE性质的高效红光分子的合成及细胞成像 (45)2.1引言 (45)2.2实验部分 (46)2.3结果与讨论 (49)2.4本章小结 (57)2.5参考文献 (60)第3章基于AIE染料的RNS荧光探针的合成及性质研究 (62)3.1引言 (62)3.2实验部分 (63)3.3结果与讨论 (65)3.4本章小结 (70)3.5参考文献 (71)第4章结论 (74)作者简介 (83)致谢 (84)41第1章前言1.1引言人们在分子水平上理解基本的发光过程已经取得了显著的成就。

BAM7_SDS_MedChemExpress

Inhibitors, Agonists, Screening LibrariesSafety Data Sheet Revision Date:May-24-2017Print Date:May-24-20171. PRODUCT AND COMPANY IDENTIFICATION1.1 Product identifierProduct name :BAM7Catalog No. :HY-15341CAS No. :331244-89-41.2 Relevant identified uses of the substance or mixture and uses advised againstIdentified uses :Laboratory chemicals, manufacture of substances.1.3 Details of the supplier of the safety data sheetCompany:MedChemExpress USATel:609-228-6898Fax:609-228-5909E-mail:sales@1.4 Emergency telephone numberEmergency Phone #:609-228-68982. HAZARDS IDENTIFICATION2.1 Classification of the substance or mixtureGHS Classification in accordance with 29 CFR 1910 (OSHA HCS)Acute toxicity, Oral (Category 4),H302Acute aquatic toxicity (Category 1),H400Chronic aquatic toxicity (Category 1),H4102.2 GHS Label elements, including precautionary statementsPictogramSignal word WarningHazard statement(s)H302 Harmful if swallowed.H410 Very toxic to aquatic life with long lasting effects.Precautionary statement(s)P264 Wash skin thoroughly after handling.P270 Do not eat, drink or smoke when using this product.P273 Avoid release to the environment.P301 + P312 IF SWALLOWED: Call a POISON CENTER or doctor/ physician if you feel unwell.P330 Rinse mouth.P391 Collect spillage.P501 Dispose of contents/ container to an approved waste disposal plant.2.3 Other hazardsNone.3. COMPOSITION/INFORMATION ON INGREDIENTS3.1 SubstancesSynonyms:BAM 7; BAM⁻7Formula:C21H19N5O2SMolecular Weight:405.47CAS No. :331244-89-44. FIRST AID MEASURES4.1 Description of first aid measuresEye contactRemove any contact lenses, locate eye-wash station, and flush eyes immediately with large amounts of water. Separate eyelids with fingers to ensure adequate flushing. Promptly call a physician.Skin contactRinse skin thoroughly with large amounts of water. Remove contaminated clothing and shoes and call a physician.InhalationImmediately relocate self or casualty to fresh air. If breathing is difficult, give cardiopulmonary resuscitation (CPR). Avoid mouth-to-mouth resuscitation.IngestionWash out mouth with water; Do NOT induce vomiting; call a physician.4.2 Most important symptoms and effects, both acute and delayedThe most important known symptoms and effects are described in the labelling (see section 2.2).4.3 Indication of any immediate medical attention and special treatment neededTreat symptomatically.5. FIRE FIGHTING MEASURES5.1 Extinguishing mediaSuitable extinguishing mediaUse water spray, dry chemical, foam, and carbon dioxide fire extinguisher.5.2 Special hazards arising from the substance or mixtureDuring combustion, may emit irritant fumes.5.3 Advice for firefightersWear self-contained breathing apparatus and protective clothing.6. ACCIDENTAL RELEASE MEASURES6.1 Personal precautions, protective equipment and emergency proceduresUse full personal protective equipment. Avoid breathing vapors, mist, dust or gas. Ensure adequate ventilation. Evacuate personnel to safe areas.Refer to protective measures listed in sections 8.6.2 Environmental precautionsTry to prevent further leakage or spillage. Keep the product away from drains or water courses.6.3 Methods and materials for containment and cleaning upAbsorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); Decontaminate surfaces and equipment by scrubbing with alcohol; Dispose of contaminated material according to Section 13.7. HANDLING AND STORAGE7.1 Precautions for safe handlingAvoid inhalation, contact with eyes and skin. Avoid dust and aerosol formation. Use only in areas with appropriate exhaust ventilation.7.2 Conditions for safe storage, including any incompatibilitiesKeep container tightly sealed in cool, well-ventilated area. Keep away from direct sunlight and sources of ignition.Recommended storage temperature:Powder-20°C 3 years4°C 2 yearsIn solvent-80°C 6 months-20°C 1 monthShipping at room temperature if less than 2 weeks.7.3 Specific end use(s)No data available.8. EXPOSURE CONTROLS/PERSONAL PROTECTION8.1 Control parametersComponents with workplace control parametersThis product contains no substances with occupational exposure limit values.8.2 Exposure controlsEngineering controlsEnsure adequate ventilation. Provide accessible safety shower and eye wash station.Personal protective equipmentEye protection Safety goggles with side-shields.Hand protection Protective gloves.Skin and body protection Impervious clothing.Respiratory protection Suitable respirator.Environmental exposure controls Keep the product away from drains, water courses or the soil. Cleanspillages in a safe way as soon as possible.9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Information on basic physical and chemical propertiesAppearance Pink to red (Solid)Odor No data availableOdor threshold No data availablepH No data availableMelting/freezing point No data availableBoiling point/range No data availableFlash point No data availableEvaporation rate No data availableFlammability (solid, gas)No data availableUpper/lower flammability or explosive limits No data availableVapor pressure No data availableVapor density No data availableRelative density No data availableWater Solubility No data availablePartition coefficient No data availableAuto-ignition temperature No data availableDecomposition temperature No data availableViscosity No data availableExplosive properties No data availableOxidizing properties No data available9.2 Other safety informationNo data available.10. STABILITY AND REACTIVITY10.1 ReactivityNo data available.10.2 Chemical stabilityStable under recommended storage conditions.10.3 Possibility of hazardous reactionsNo data available.10.4 Conditions to avoidNo data available.10.5 Incompatible materialsStrong acids/alkalis, strong oxidising/reducing agents.10.6 Hazardous decomposition productsUnder fire conditions, may decompose and emit toxic fumes.Other decomposition products - no data available.11.TOXICOLOGICAL INFORMATION11.1 Information on toxicological effectsAcute toxicityClassified based on available data. For more details, see section 2Skin corrosion/irritationClassified based on available data. For more details, see section 2Serious eye damage/irritationClassified based on available data. For more details, see section 2Respiratory or skin sensitizationClassified based on available data. For more details, see section 2Germ cell mutagenicityClassified based on available data. For more details, see section 2CarcinogenicityIARC: No component of this product present at a level equal to or greater than 0.1% is identified as probable, possible or confirmed human carcinogen by IARC.ACGIH: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by ACGIH.NTP: No component of this product present at a level equal to or greater than 0.1% is identified as a anticipated or confirmed carcinogen by NTP.OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA.Reproductive toxicityClassified based on available data. For more details, see section 2Specific target organ toxicity - single exposureClassified based on available data. For more details, see section 2Specific target organ toxicity - repeated exposureClassified based on available data. For more details, see section 2Aspiration hazardClassified based on available data. For more details, see section 212. ECOLOGICAL INFORMATION12.1 ToxicityNo data available.12.2 Persistence and degradabilityNo data available.12.3 Bioaccumlative potentialNo data available.12.4 Mobility in soilNo data available.12.5 Results of PBT and vPvB assessmentPBT/vPvB assessment unavailable as chemical safety assessment not required or not conducted.12.6 Other adverse effectsNo data available.13. DISPOSAL CONSIDERATIONS13.1 Waste treatment methodsProductDispose substance in accordance with prevailing country, federal, state and local regulations.Contaminated packagingConduct recycling or disposal in accordance with prevailing country, federal, state and local regulations.14. TRANSPORT INFORMATIONDOT (US)This substance is considered to be non-hazardous for transport.IMDGUN number: 3077Class: 9Packing group: IIIEMS-No: F-A, S-FProper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, SOLID, N.O.S.Marine pollutant: Marine pollutantIATAUN number: 3077Class: 9Packing group: IIIProper shipping name: Environmentally hazardous substance, solid, n.o.s.15. REGULATORY INFORMATIONSARA 302 Components:No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302.SARA 313 Components:This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313.SARA 311/312 Hazards:No SARA Hazards.Massachusetts Right To Know Components:No components are subject to the Massachusetts Right to Know Act.Pennsylvania Right To Know Components:No components are subject to the Pennsylvania Right to Know Act.New Jersey Right To Know Components:No components are subject to the New Jersey Right to Know Act.California Prop. 65 Components:This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.16. OTHER INFORMATIONCopyright 2017 MedChemExpress. The above information is correct to the best of our present knowledge but does not purport to be all inclusive and should be used only as a guide. The product is for research use only and for experienced personnel. It must only be handled by suitably qualified experienced scientists in appropriately equipped and authorized facilities. The burden of safe use of this material rests entirely with the user. MedChemExpress disclaims all liability for any damage resulting from handling or from contact with this product.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。

分子生物学词汇(中英文对照表 )

Gelucire-14-44-SDS-MedChemExpress

Inhibitors, Agonists, Screening LibrariesSafety Data Sheet Revision Date:Nov.-23-2018Print Date:Nov.-23-20181. PRODUCT AND COMPANY IDENTIFICATION1.1 Product identifierProduct name :Gelucire 14/44Catalog No. :HY-Y1892CAS No. :121548-04-71.2 Relevant identified uses of the substance or mixture and uses advised againstIdentified uses :Laboratory chemicals, manufacture of substances.1.3 Details of the supplier of the safety data sheetCompany:MedChemExpress USATel:609-228-6898Fax:609-228-5909E-mail:sales@1.4 Emergency telephone numberEmergency Phone #:609-228-68982. HAZARDS IDENTIFICATION2.1 Classification of the substance or mixtureNot a hazardous substance or mixture.2.2 GHS Label elements, including precautionary statementsNot a hazardous substance or mixture.2.3 Other hazardsNone.3. COMPOSITION/INFORMATION ON INGREDIENTS3.1 SubstancesSynonyms:NoneFormula:N/AMolecular Weight:N/ACAS No. :121548-04-74. FIRST AID MEASURES4.1 Description of first aid measuresEye contactRemove any contact lenses, locate eye-wash station, and flush eyes immediately with large amounts of water. Separate eyelids with fingers to ensure adequate flushing. Promptly call a physician.Skin contactRinse skin thoroughly with large amounts of water. Remove contaminated clothing and shoes and call a physician.InhalationImmediately relocate self or casualty to fresh air. If breathing is difficult, give cardiopulmonary resuscitation (CPR). Avoid mouth-to-mouth resuscitation.IngestionWash out mouth with water; Do NOT induce vomiting; call a physician.4.2 Most important symptoms and effects, both acute and delayedThe most important known symptoms and effects are described in the labelling (see section 2.2).4.3 Indication of any immediate medical attention and special treatment neededTreat symptomatically.5. FIRE FIGHTING MEASURES5.1 Extinguishing mediaSuitable extinguishing mediaUse water spray, dry chemical, foam, and carbon dioxide fire extinguisher.5.2 Special hazards arising from the substance or mixtureDuring combustion, may emit irritant fumes.5.3 Advice for firefightersWear self-contained breathing apparatus and protective clothing.6. ACCIDENTAL RELEASE MEASURES6.1 Personal precautions, protective equipment and emergency proceduresUse full personal protective equipment. Avoid breathing vapors, mist, dust or gas. Ensure adequate ventilation. Evacuate personnel to safe areas.Refer to protective measures listed in sections 8.6.2 Environmental precautionsTry to prevent further leakage or spillage. Keep the product away from drains or water courses.6.3 Methods and materials for containment and cleaning upAbsorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); Decontaminate surfaces and equipment by scrubbing with alcohol; Dispose of contaminated material according to Section 13.7. HANDLING AND STORAGE7.1 Precautions for safe handlingAvoid inhalation, contact with eyes and skin. Avoid dust and aerosol formation. Use only in areas with appropriate exhaust ventilation.7.2 Conditions for safe storage, including any incompatibilitiesKeep container tightly sealed in cool, well-ventilated area. Keep away from direct sunlight and sources of ignition.Recommended storage temperature:Pure form-20°C 3 years4°C 2 yearsIn solvent-80°C 6 months-20°C 1 monthShipping at room temperature if less than 2 weeks.7.3 Specific end use(s)No data available.8. EXPOSURE CONTROLS/PERSONAL PROTECTION8.1 Control parametersComponents with workplace control parametersThis product contains no substances with occupational exposure limit values.8.2 Exposure controlsEngineering controlsEnsure adequate ventilation. Provide accessible safety shower and eye wash station.Personal protective equipmentEye protection Safety goggles with side-shields.Hand protection Protective gloves.Skin and body protection Impervious clothing.Respiratory protection Suitable respirator.Environmental exposure controls Keep the product away from drains, water courses or the soil. Cleanspillages in a safe way as soon as possible.9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Information on basic physical and chemical propertiesAppearance White to off-white (Oil)Odor No data availableOdor threshold No data availablepH No data availableMelting/freezing point No data availableBoiling point/range No data availableFlash point No data availableEvaporation rate No data availableFlammability (solid, gas)No data availableUpper/lower flammability or explosive limits No data availableVapor pressure No data availableVapor density No data availableRelative density No data availableWater Solubility No data availablePartition coefficient No data availableAuto-ignition temperature No data availableDecomposition temperature No data availableViscosity No data availableExplosive properties No data availableOxidizing properties No data available9.2 Other safety informationNo data available.10. STABILITY AND REACTIVITY10.1 ReactivityNo data available.10.2 Chemical stabilityStable under recommended storage conditions.10.3 Possibility of hazardous reactionsNo data available.10.4 Conditions to avoidNo data available.10.5 Incompatible materialsStrong acids/alkalis, strong oxidising/reducing agents.10.6 Hazardous decomposition productsUnder fire conditions, may decompose and emit toxic fumes.Other decomposition products - no data available.11.TOXICOLOGICAL INFORMATION11.1 Information on toxicological effectsAcute toxicityClassified based on available data. For more details, see section 2Skin corrosion/irritationClassified based on available data. For more details, see section 2Serious eye damage/irritationClassified based on available data. For more details, see section 2Respiratory or skin sensitizationClassified based on available data. For more details, see section 2Germ cell mutagenicityClassified based on available data. For more details, see section 2CarcinogenicityIARC: No component of this product present at a level equal to or greater than 0.1% is identified as probable, possible or confirmed human carcinogen by IARC.ACGIH: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by ACGIH.NTP: No component of this product present at a level equal to or greater than 0.1% is identified as a anticipated or confirmed carcinogen by NTP.OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA.Reproductive toxicityClassified based on available data. For more details, see section 2Specific target organ toxicity - single exposureClassified based on available data. For more details, see section 2Specific target organ toxicity - repeated exposureClassified based on available data. For more details, see section 2Aspiration hazardClassified based on available data. For more details, see section 212. ECOLOGICAL INFORMATION12.1 ToxicityNo data available.12.2 Persistence and degradabilityNo data available.12.3 Bioaccumlative potentialNo data available.12.4 Mobility in soilNo data available.12.5 Results of PBT and vPvB assessmentPBT/vPvB assessment unavailable as chemical safety assessment not required or not conducted.12.6 Other adverse effectsNo data available.13. DISPOSAL CONSIDERATIONS13.1 Waste treatment methodsProductDispose substance in accordance with prevailing country, federal, state and local regulations.Contaminated packagingConduct recycling or disposal in accordance with prevailing country, federal, state and local regulations.14. TRANSPORT INFORMATIONDOT (US)This substance is considered to be non-hazardous for transport.IMDGThis substance is considered to be non-hazardous for transport.IATAThis substance is considered to be non-hazardous for transport.15. REGULATORY INFORMATIONSARA 302 Components:No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302.SARA 313 Components:This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313.SARA 311/312 Hazards:No SARA Hazards.Massachusetts Right To Know Components:No components are subject to the Massachusetts Right to Know Act.Pennsylvania Right To Know Components:No components are subject to the Pennsylvania Right to Know Act.New Jersey Right To Know Components:No components are subject to the New Jersey Right to Know Act.California Prop. 65 Components:This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.16. OTHER INFORMATIONCopyright 2018 MedChemExpress. The above information is correct to the best of our present knowledge but does not purport to be all inclusive and should be used only as a guide. The product is for research use only and for experienced personnel. It must only be handled by suitably qualified experienced scientists in appropriately equipped and authorized facilities. The burden of safe use of this material rests entirely with the user. MedChemExpress disclaims all liability for any damage resulting from handling or from contact with this product.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。

四丁基氢氧化铵化学品安全技术说明书

化学品安全技术说明书产品名称: 四丁基氢氧化铵按照GB/T 16483、GB/T 17519 编制修订日期: 2019年7月15日版本: 1.0最初编制日期: 2019年7月15日第1部分化学品及企业标识化学品中文名：四丁基氢氧化铵化学品英文名： Tetrabutylammonium hydroxide产品编号： -企业名称：上海百舜生物科技有限公司企业地址：上海奉贤区柘林镇联业路918弄26号邮编： 201400传真：联系电话：电子邮件地址：企业应急电话：产品推荐及限制用途：工业及科研用途。

第2部分危险性概述紧急情况概述：易燃液体和蒸气。

吞咽有害。

造成严重皮肤灼伤和眼损伤。

GHS危险性类别：易燃液体类别 3急性经口毒性类别 4皮肤腐蚀 / 刺激类别 1B严重眼损伤 / 眼刺激类别 1标签要素：象形图：警示词：危险危险性说明：H226 易燃液体和蒸气H302 吞咽有害H314 造成严重皮肤灼伤和眼损伤防范说明：预防措施：—— P210 远离热源/火花/明火/热表面。

禁止吸烟。

—— P233 保持容器密闭。

—— P240 容器和装载设备接地/等势联接。

—— P241 使用防爆的电气/通风/照明/设备。

—— P242 只能使用不产生火花的工具。

—— P243 采取防止静电放电的措施。

—— P280 戴防护手套/穿防护服/戴防护眼罩/戴防护面具。

—— P264 作业后彻底清洗。

—— P270 使用本产品时不要进食、饮水或吸烟。

—— P260 不要吸入粉尘/烟/气体/烟雾/蒸气/喷雾。

事故响应：—— P303+P361+P353 如皮肤(或头发)沾染：立即脱掉所有沾染的衣服。

用水清洗皮肤/淋浴。

—— P370+P378 火灾时：使用灭火器灭火。

—— P301+P312 如误吞咽：如感觉不适，呼叫解毒中心/ 医生—— P330 漱口。

—— P301+P330+P331 如误吞咽：漱口。

不要诱导呕吐。

—— P363 沾染的衣服清洗后方可重新使用。

玛巴洛沙韦结构式

玛巴洛沙韦结构式全文共四篇示例，供读者参考第一篇示例：玛巴洛沙韦（Mavlabosavir，又称Pimodivir）是一种广谱的抗流感病毒药物，属于口服的新型RNA干扰剂。

其化学结构式为C23H26FN7O2，分子量为449.499 g/mol。

玛巴洛沙韦如今已被证实对包括甲型和乙型流感病毒在内的多种流感病毒具有很强的抑制作用。

它采用一种独特的机制来阻断病毒的生长和复制，从而有效地减轻病毒感染的症状。

玛巴洛沙韦的化学结构体现了其抗流感病毒的作用机制。

该药物是一种强效的非核苷类反转录酶抑制剂，通过干扰流感病毒的RNA复制而达到抑制病毒生长的效果。

其结构中包含有一个异氮杂环和多个氟原子，这些特殊的结构单元赋予了玛巴洛沙韦出色的抗病毒活性。

从结构上看，玛巴洛沙韦的核心结构是一个含氮杂环的环戊烯酮（cyclopentenone），在环戊烯的位置上连接有一个含氟的芳香族环。

这种结构形式为玛巴洛沙韦提供了非常强的疏水性，使其能够在病毒颗粒内部精准地与反转录酶结合，进而阻断病毒的复制与传播。

在化学结构中还包含有一个异噻唑环和多个取代基。

异噻唑环是一种含硫杂环结构，能够增强分子的稳定性和生物活性。

这些取代基对分子的生物活性及亲合力也起到了关键的作用，通过特定的相互作用与病毒RNA或蛋白结合，最终实现抗病毒作用。

玛巴洛沙韦的化学结构具有独特的设计，使其在与流感病毒的特定靶标相互作用时能够表现出卓越的活性。

通过对病毒复制过程的干扰，玛巴洛沙韦有效地抑制了病毒的生长，为治疗流感提供了一种新的选择。

随着对其药效和安全性的进一步研究，玛巴洛沙韦有望成为未来治疗流感的重要药物之一。

【参考资料来源于维基百科等网站】。

第二篇示例：玛巴洛沙韦（Mavrolashavi）是一种抗病毒药物，广泛用于治疗各种病毒性疾病。

它主要用于治疗艾滋病毒感染和流感等病毒感染。

玛巴洛沙韦的结构式为C44H46F2N6O8，化学式为C44H46F2N6O8，分子量为810.871。

封闭添加试剂(按字母顺序排列)

50mg
询价
4、BMPA
改变巯基基团为羧基基团，用于制备肽段-蛋白质交联物。
产品特点：
•反应基团：马来酰亚胺和羧基
•反应指向：巯基基团和胺（当与EDC结合使用时）
参考文献
Hermanson, G.T. (2008). Bioconjugate Techniques, 2nd ed., Elsevier Inc., pp.111-113. (Product # 20036)
25g
473
相关产品：
产品货号
产品名称
价格￥
24510
Sulfo-NHS
1848
22980
EDC
1005
20320
DCC
488
14、STAT，SATP和巯基添加试剂盒
添加保护性巯基防止二肽形成。
产品特点：
•与伯胺反应添加保护性巯基
•简单的脱保护步骤即可产生游离的巯基
•Thermo Scientific巯基添加试剂盒包含硫醇化作用，脱保护，纯化和定量所有需要的组分
订购信息：
产品货号
产品名称
包装
价格￥
23031
二盐酸乙二胺
10g
399
8、碘乙酰胺（Iodoacetamide），一次性使用
质谱前可靠的烷基化试剂。产品ຫໍສະໝຸດ 点：•与巯基基团形成共价键
•质谱级别（高纯度）
•方便，一次性使用形式（3个微型管，每管含有9.4mg）
•当用132μl碳酸氢铵（ammonium bicarbonate）溶解时，每管产生375mM的溶液
500mg
620
10、MMTS
可与巯基反应的可逆试剂。
产品特点：
•将-SH基团转化为-S-S-CH3

7-(乙基氨基)-4-甲基香豆素

7-(乙基氨基)-4-甲基香豆素是一种重要的有机合成中间体，也是一种重要的医药原料。

它是香豆素类衍生物中的一种，其分子式为C11H13NO2，分子量为191.23。

下面将从以下几个方面对7-(乙基氨基)-4-甲基香豆素进行介绍。

一、化学性质1. 7-(乙基氨基)-4-甲基香豆素的结构特点7-(乙基氨基)-4-甲基香豆素的分子结构中含有乙基氨基和甲基基团，这两个基团的存在赋予了它许多特殊的化学性质。

2. 化学反应在一系列化学试剂作用下，7-(乙基氨基)-4-甲基香豆素可以发生不同的化学反应，如烷基化、羟基化、氨基化等，从而衍生出多种不同的化合物。

这些化合物在医药、农药等领域具有重要的应用价值。

二、制备方法目前，关于7-(乙基氨基)-4-甲基香豆素的制备方法已有多种报道，其中以合成路线简洁、收率较高的方法较为广泛应用。

常见的制备方法包括：1. 从香豆素出发，经过若干步反应得到7-(乙基氨基)-4-甲基香豆素。

2. 通过合成路线中的键合反应和官能团变换，将简单的有机化合物转化为目标产物。

三、应用领域由于7-(乙基氨基)-4-甲基香豆素具有较好的生物活性和理化性质，因此在医药和农药领域有着广泛的应用：1. 医药领域：7-(乙基氨基)-4-甲基香豆素及其衍生物对肿瘤、炎症等疾病具有一定的治疗作用，且其结构可以作为药物分子的合成前体。

2. 农药领域：7-(乙基氨基)-4-甲基香豆素及其衍生物对农作物害虫、杂草等具有较好的杀灭作用，可作为高效、低毒的农药原料。

四、市场前景当前，随着医药和农药行业的发展，对于生物活性分子的需求日益增加，7-(乙基氨基)-4-甲基香豆素及其衍生物将有着广阔的市场前景。

其在有机合成领域的重要性也日益凸显，预计其市场需求将继续保持增长态势。

7-(乙基氨基)-4-甲基香豆素作为一种重要的有机合成中间体，具有重要的化学性质、制备方法和应用领域。

随着医药和农药行业的不断发展，其市场前景广阔。

UHPLC－MS

ＵＨＰＬＣ－ＭＳ/ＭＳ法测定瑞戈非尼中两种痕量基因毒性杂质陈爽ꎬ刘柱ꎬ石云峰ꎬ朱价ꎬ罗英(浙江省食品药品检验研究院ꎬ浙江杭州３１００５８)摘要:目的㊀建立超高效液相色谱－串联质谱(ＵＨＰＬＣ－ＭＳ/ＭＳ)方法测定瑞戈非尼中两类基因毒性杂质[３－氟－４－氨基苯酚(ＳＭ２)㊁３－三氟甲基－４－氯异氰酸苯酯(ＳＭ３)]的含量ꎮ方法㊀采用色谱柱ＡｇｉｌｅｎｔＲＲＨＤＣ１８(２.１ｍｍˑ１００ｍｍꎬ１.８μｍ)ꎬ流动相为０.０５％甲酸水－甲醇ꎬ梯度洗脱ꎬ流速为０.３ｍＬｍｉｎ－１ꎬ柱温为３５ħꎻ采用Ａｇｉｌｅｎｔ１２９０－６４７０Ａ液质联用仪和电喷雾离子源(ＡＪＳＥＳＩ)源检测ꎬ正负离子模式采集数据ꎮ结果㊀本方法的专属性㊁线性与范围㊁定量限与检测限㊁准确度㊁精密度及稳定性均符合«中国药典»的验证指标ꎮ结论㊀本方法操作简便ꎬ结果可靠ꎬ用于两批瑞戈非尼中潜在毒性杂质(３－氟－４－氨基苯酚㊁３－三氟甲基－４－氯异氰酸苯酯)的测定ꎮ两批样品中均未检测到ＳＭ２ꎬ而基因毒性杂质ＳＭ３的含量分别为１３.６ˑ１０－６和４１.４ˑ１０－６ꎮ关键词:瑞戈非尼ꎻ基因毒性杂质ꎻ超高效液相色谱－串联质谱中图分类号:Ｒ９２７.１㊀文献标志码:Ａ㊀文章编号:２０９５－５３７５(２０２３)０７－０４８５－００５ｄｏｉ:１０.１３５０６/ｊ.ｃｎｋｉ.ｊｐｒ.２０２３.０７.０１０ＤｅｔｅｒｍｉｎａｔｉｏｎｏｆｔｗｏｔｒａｃｅｇｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｉｅｓｉｎＲｅｇｏｒａｆｅｎｉｂｂｙＵＨＰＬＣ－ＭＳ/ＭＳＣＨＥＮＳｈｕａｎｇꎬＬＩＵＺｈｕꎬＳＨＩＹｕｎｆｅｎｇꎬＺＨＵＪｉａꎬＬＵＯＹｉｎｇ(ＺｈｅｊｉａｎｇＩｎｓｔｉｔｕｔｅｆｏｒＦｏｏｄａｎｄＤｒｕｇＣｏｎｔｒｏｌꎬＨａｎｇｚｈｏｕ３１００５８ꎬＣｈｉｎａ)Ａｂｓｔｒａｃｔ:Ｏｂｊｅｃｔｉｖｅ㊀ＴｏｅｓｔａｂｌｉｓｈａｎＵＨＰＬＣ－ＭＳ/ＭＳａｎａｌｙｔｉｃａｌｍｅｔｈｏｄｆｏｒｔｈｅｄｅｔｅｒｍｉｎａｔｉｏｎｏｆｇｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｉｅｓｉｎＲｅｇｏｒａｆｅｎｉｂ.Ｍｅｔｈｏｄｓ㊀ＴｈｅｍｅｔｈｏｄｗａｓａｃｈｉｅｖｅｄｏｎａＡｇｉｌｅｎｔＲＲＨＤＣ１８ｃｏｌｕｍｎ(２.１ｍｍˑ１００ｍｍꎬ１.８μｍ)ｕｔｉｌｉｚｉｎｇａｍｏｂｉｌｅｐｈａｓｅｏｆ０.０５％Ｆｏｒｍｉｃａｃｉｄｗａｔｅｒ(Ａ)－Ｍｅｔｈａｎｏｌ(Ｂ)ｗｉｔｈｇｒａｄｉｅｎｔｅｌｕｔｉｏｎａｔｔｈｅｆｌｏｗｒａｔｅｏｆ０.３ｍＬｍｉｎ-１.Ｔｈｅｔｅｍｐｅｒａｔｕｒｅｏｆｃｏｌｕｍｎｗａｓｓｅｔａｔ３５ħ.ＴｈｅＡｇｉｌｅｎｔ１２９０－６４７０ＡＬＣ－ＭＳｗａｓｕｓｅｄｔｏｄｅｔｅｃｔ(ＡＪＳＥＳＩｓｏｕｒｃｅꎬｉｎＭｕｌｔｉｐｌｅＲｅａｃｔｉｏｎＭｏｎｉｔｏｒｉｎｇｍｏｄｅ).Ｒｅｓｕｌｔｓ㊀ＴｈｅｓｐｅｃｉｆｉｃｉｔｙꎬｌｉｎｅａｒｉｔｙａｎｄｒａｎｇｅꎬＬＯＱａｎｄＬＯＤꎬａｃｃｕｒａｃｙꎬｐｒｅｃｉｓｉｏｎａｎｄｓｔａｂｉｌｉｔｙｏｆｔｈｅｍｅｔｈｏｄｗｅｒｅａｌｌｉｎａｃｃｏｒｄａｎｃｅｗｉｔｈｔｈｅｖａｌｉｄａｔｉｏｎｏｆＣｈｉｎｅｓｅＰｈａｒｍａｃｏｐｏｅｉａ.Ｃｏｎｃｌｕｓｉｏｎ㊀Ｔｈｅｐｒｏｐｏｓｅｄｍｅｔｈｏｄｗａｓｓｕｃｃｅｓｓｆｕｌｌｙａｐｐｌｉｅｄｔｏｄｅｔｅｒｍｉｎｅｔｈｅｔｒａｃｅ－ｌｅｖｅｌＰＧＩｓｉｎｔｗｏｂａｔｃｈｅｓｏｆｒｅｇｏｒａｆｅｎｉｂ.ＴｈｅｃｏｎｔｅｎｔｓｏｆＳＭ２ｗｅｒｅｎｏｔｏｂｓｅｒｖｅｄｉｎｔｈｅｔｗｏｂａｔｃｈｅｓｏｆｓａｍｐｌｅｓꎬｗｈｅｒｅａｓｔｈｅｃｏｎｔｅｎｔｓｏｆＳＭ３ｗｅｒｅｄｅｔｅｒｍｉｎｅｄｔｏｂｅ１３.６ˑ１０－６ａｎｄ４１.４ˑ１０－６ꎬｒｅｓｐｅｃｔｉｖｅｌｙ.Ｋｅｙｗｏｒｄｓ:ＲｅｇｏｒａｆｅｎｉｂꎻＧｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｙꎻＵＨＰＬＣ－ＭＳ/ＭＳ㊀㊀基因毒性杂质(或遗传毒性杂质ꎬｇｅｎｏｔｏｘｉｃｉｍ￣ｐｕｒｉｔｙꎬＧＴＩ)是少量即能引起细胞ＤＮＡ损伤ꎬ诱导基因突变ꎬ并具有致癌倾向的化合物[１]ꎮ欧洲药品管理局(ＥＭＥＡ)㊁美国食品药品管理局(ＦＤＡ)及人用药品注册技术要求国际协调会(ＩＣＨ)先后颁布了基因毒性杂质控制的指导文件[２－４]ꎬ推荐以毒理学关注阈值(ＴＴＣꎬ１.５μｇｄ－１)来控制用药风险ꎬ并发布基因毒性警示结构基团ꎮ瑞戈非尼(Ｒｅｇｏｒａｆｅｎｉｂ)是拜耳药业研发并于２０１７年３月在国内上市的一种新型口服多靶点的磷酸激酶抑制剂ꎬ本品以促进肿瘤血管生成和细胞增殖的多种蛋白激酶为靶标ꎬ达到治疗晚期及转移性结肠癌㊁进展期肝细胞癌㊁胃肠道恶性间质肿瘤㊁儿童神经母细胞瘤和胶质母细胞瘤及一些转移性实体肿瘤的目的ꎮ瑞戈非尼的合成路线中起始物料ＳＭ２㊁ＳＭ３结构中均含有苯胺类基因毒性警示结构基团ꎬ具有潜在基因毒性ꎬ详见图１ꎮ瑞戈非尼已收载于«中国药典»和«欧洲药典»ꎬ已经报道了一种ＬＣ－ＭＳ/ＭＳ法定量同时测定肝细胞癌患者血浆中瑞戈非尼中及其两种活性代谢物的含量的方法[１７]ꎬ但目前也未见相关文献报道本品中两种苯胺类基因毒性杂质ＳＭ２㊁ＳＭ３的测定方法ꎮ㊀作者简介:陈爽ꎬ女ꎬ硕士ꎬ副主任药师ꎬ研究方向:药物质量研究㊁标准提高研究ꎬＥ－ｍａｉｌ:ｃｒｅｄｅａｒ＠１２６.ｃｏｍＡ.３－氟－４－氨基苯酚(ＳＭ２)ꎻＢ.３－三氟甲基－４－氯异氰酸苯酯(ＳＭ３)图１㊀瑞戈非尼中苯胺类基因毒性杂质结构因此建立超高效液相色谱－串联质谱(ＵＨＰＬＣ－ＭＳ/ＭＳ)方法对瑞戈非尼中少量的苯胺类基因毒性杂质的含量进行控制ꎮ本研究依照ＩＣＨ推荐的条件ꎬ建立了方法并从方法的专属性㊁溶液稳定性㊁线性与范围㊁定量限与检测限㊁准确度㊁精密度方面进行了方法学研究ꎬ本法灵敏㊁可靠㊁简便ꎬ为瑞戈非尼工艺过程控制和质量保障提供参考依据ꎮ１㊀仪器与试剂Ａｇｉｌｅｎｔ１２９０－６４７０ＡＬＣ－ＭＳ联用系统(美国安捷伦)ꎬ配备电喷雾离子源(ＡＪＳＥＳＩ)ꎬ质谱软件为ＡｇｉｌｅｎｔＭａｓｓＨｕｎｔｅｒ工作站ꎻＸＳ２０５ＤＵ百万分之一电子天平(瑞士梅特勒托利多公司)ꎮＡｇｉｌｅｎｔＲＲＨＤＣ１８(２.１ｍｍˑ１００ｍｍꎬ１.８μｍꎬ填料:十八烷基硅烷键合硅胶ꎻＡｇｉｌｅｎｔ公司)ꎮ３－氟－４－氨基苯酚对照品(批号:Ｐ１１５６８１１ꎬ纯度:９８％)ꎬ３－三氟甲基－４－氯异氰酸苯酯对照品(杭州华东医药集团新药研究院有限公司ꎬ批号:１９１２０１ꎬ纯度:９９.７６％)ꎻ瑞戈非尼(批号:ＲＧＦＮ－Ｂ－１９０９０１㊁Ｚ１９３－Ａ１９１１００１ꎬ由Ａ公司提供)ꎻ甲醇(默克试剂有限公司)㊁异丙醇㊁甲酸(阿拉丁有限公司)均为色谱级ꎮ２㊀方法与结果２.１㊀色谱条件㊀液相色谱柱:ＡｇｉｌｅｎｔＲＲＨＤＣ１８(２.１ｍｍˑ１００ｍｍꎬ１.８μｍ)ꎻ流速０.３ｍＬｍｉｎ－１ꎻ０.０５％甲酸水为流动相Ａꎬ甲醇为流动相Ｂꎬ梯度洗脱(０~１.２ｍｉｎꎬ１０％Ｂꎻ１.２~４.０ｍｉｎꎬ１０％Ｂң６０％Ｂꎻ４.０~８.０ｍｉｎꎬ６０％Ｂꎻ８.０~１３.０ｍｉｎꎬ９５％Ｂꎻ１３.０~１３.１０ｍｉｎꎬ９５％Ｂң１０％Ｂꎻ１３.１０~１５.０ｍｉｎꎬ１０％Ｂ)ꎻ柱温３５ħꎻ进样体积５μＬꎮ取０.６ｎｇｍＬ－１混标对照品溶液ꎬ在ＭＲＭ模式下进样分析ꎬ结果如图２所示ꎬ各杂质之间分离度良好ꎮ２.２㊀质谱条件㊀采用电喷雾离子源(ＡＪＳＥＳＩ)ꎬ正负离子检测模式ＭＲＭ采集(ＳＭ２正离子模式㊁ＳＭ３㊀ＳＭ２[３－氟－４－氨基苯酚(３－Ｆｌｕｏｒｏ－４－ａｍｉｎｏｐｈｅｎｏｌ)]ꎻＳＭ３[３－三氟甲基－４－氯异氰酸苯酯(３－ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌ－４－ｐｈｅｎｙｌ￣ｃｈｌｏｒｏｉｓｏｃｙａｎａｔｅ)]图２㊀混合对照品溶液总离子流图负离子模式)ꎬ参数见表１ꎮ喷雾电压为３.５ｋＶꎬ鞘气为２５０ħꎬ鞘气流速为１１Ｌｍｉｎ－１ꎬ雾化气为４５ｐｓｉꎬ干燥气温度为３００ħꎬ干燥气流速为５Ｌｍｉｎ－１ꎮ母离子及子离子:取０.６μｇｍＬ－１混标对照品溶液ꎬ在Ｓｃａｎ模式下进样ꎬ进行ＭＳ分析ꎬ两种基因毒性杂质的质谱图如图４所示ꎬ其中３－氟－４－氨基苯酚的母离子为ｍ/ｚ１２８.０５ꎬ３－三氟甲基－４－氯异氰酸苯酯的母离子为ｍ/ｚ２８０.００ꎮ各基因毒性杂质的ＭＲＭ参数见表１ꎬ定量离子及定性离子的选择见表１ꎮ表１㊀ＭＲＭ采集参数设置化合物类型母离子(ｍ/ｚ)子离子(ｍ/ｚ)碰撞能量/ｅＶ碎裂电压/Ｖ扫描时间/ｍｓＳＭ２(ＥＳＩ＋)ＳＭ３(ＥＳＩ－)定量离子１２８.０５１０８１７定性离子１２８.０５８１.１２５定量离子２８０２１９.９１３定性离子２８０１９９.９２５８５１１２１００㊀ＳＭ２[３－氟－４－氨基苯酚(３－ｆｌｕｏｒｏ－４－ａｍｉｎｏｐｈｅｎｏｌ)]ꎻＳＭ３[３－三氟甲基－４－氯异氰酸苯酯(３－ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌ－４－ｐｈｅｎｙｌ￣ｃｈｌｏｒｏｉｓｏｃｙａｎａｔｅ)]图３㊀两种基因毒性杂质的质谱图２.３㊀混标对照品溶液㊀精密称取３－氟－４－氨基苯酚对照品㊁３－三氟甲基－４－氯异氰酸苯酯对照品各约６ｍｇꎬ加稀释剂异丙醇溶解并稀释成６ｎｇｍＬ－１的混标对照品储备液ꎮ精密量取适量ꎬ稀释１０倍ꎬ作为０.６ｎｇｍＬ－１混标对照品溶液ꎮ２.４㊀供试品溶液㊀取本品约２０ｍｇꎬ精密称定ꎬ置２０ｍＬ容量瓶ꎬ用稀释剂溶解并稀释到刻度ꎬ摇匀ꎻ再精密量取０.１ｍＬꎬ置１０ｍＬ容量瓶ꎮ异丙醇稀释至刻度ꎬ摇匀ꎬ作为供试品溶液(１０μｇｍＬ－１)ꎮ２.５㊀１００％加标供试品溶液㊀取本品约２０ｍｇꎬ精密称定ꎬ置２０ｍＬ量瓶中ꎬ用异丙醇溶解稀释至刻度ꎬ摇匀ꎻ再精密量取０.１ｍＬꎬ置１０ｍＬ容量瓶ꎬ加入１ｍＬ对照品储备液后ꎬ再用异丙醇稀释至刻度ꎬ摇匀ꎬ作为１００％加标供试品溶液ꎮ２.６㊀方法学考察㊀２.６.１㊀专属性试验㊀取稀释剂照上述条件进行试验ꎬ记录色谱图ꎬ结果显示稀释剂不干扰测定ꎬ表明该方法专属性良好ꎮ２.６.２㊀线性关系㊁检测限和定量限㊀精密量取混标对照品储备液适量ꎬ加稀释剂稀释得到浓度分别为０.１５㊁０.３㊁０.４５㊁０.６㊁０.９㊁１.２ｎｇｍＬ－１的混标对照品溶液ꎬ进样分析ꎬ绘制标准曲线ꎬ得线性方程(见表２)ꎮ逐步稀释ꎬ考察定量限及检测限(见图４)ꎮ表２㊀瑞戈非尼中两种基因毒性杂质的线性范围㊁定量检测限及精密度参数ＳＭ２ＳＭ３线性方程Ｙ＝４７９９.５Ｘ＋２７.１Ｙ＝８９３.３Ｘ＋２７.１范围/ｎｇｍＬ－１０.１５~１.１７０.１５~１.１９ｒ０.９９９９０.９９９１检测限/ｎｇｍＬ－１０.０６０.０６定量限/ｎｇｍＬ－１０.１５０.１５精密度ＲＳＤ(％)１.３２１.９７中间精密度ＲＳＤ(％)２.５３２.２４图４㊀定量限和检测限ＭＲＭ质谱图２.６.３㊀稳定性试验㊀取２.３项下０.６ｎｇｍＬ－１的混标对照品溶液ꎬ ２.５项下１０μｇｍＬ－１的１００％加标供试品溶液ꎬ连续进样１６ｈ进行分析ꎬ各峰面积偏离度的绝对值在８ｈ内均小于１７.２２％ꎬ表明对照品溶液和１００％加标供试品溶液在８ｈ内稳定性良好ꎮ２.６.４㊀准确度和精密度试验㊀精密称取瑞戈非尼(批号:ＲＧＦＮ－Ｂ－１９０９０１㊁Ｚ１９３－Ａ１９１１００１)约２０ｍｇꎬ一式１２份ꎬ分别置２０ｍＬ量瓶中ꎬ用异丙醇溶解稀释至刻度ꎬ摇匀ꎻ再精密量取０.１ｍＬꎬ置１０ｍＬ容量瓶ꎬ精密加入２.３项下浓度为６ｎｇｍＬ－１的混标对照品储备液溶液０.２５㊁０.５㊁１.０㊁１.５ｍＬꎬ分别溶解并稀释至刻度ꎬ摇匀ꎬ即得低(０.１５ｎｇｍＬ－１ꎬ３份)㊁中(０.３０ｎｇｍＬ－１ꎬ３份)㊁高(０.６０ｎｇｍＬ－１ꎬ３份)㊁极高(０.９０ｎｇｍＬ－１ꎬ３份)４个浓度的供试品加标溶液ꎬ取混标对照品溶液和各加标供试品溶液分别进样分析ꎬ外标法计算回收率结果见表３ꎬ各基因毒性杂质回收率均在９０.６４％~１０５.４４％之间ꎬＲＳＤ均小于３.５０％ꎬ表明各基因毒性杂质回收率和精密度良好ꎮ２.７㊀样品测定㊀取瑞戈非尼供试品２批(批号:ＲＧＦＮ－Ｂ－１９０９０１㊁Ｚ１９３－Ａ１９１１００１)ꎬ每批精密称取２份约２０ｍｇꎬ置２０ｍＬ量瓶中ꎬ加稀释剂溶解并稀释至刻度ꎬ摇匀ꎻ再精密量取０.１ｍＬꎬ置１０ｍＬ容量瓶ꎬ异丙醇稀释至刻度ꎬ摇匀ꎬ作为供试品溶液(１０μｇｍＬ－１)ꎬ进样分析ꎬ结果２批次瑞戈非尼中ＳＭ２均未检出ꎬＳＭ３均有检出(见表４)ꎮ表３㊀瑞戈非尼中各基因毒性杂质的回收率化合物加入量测得量回收率平均回收ＲＳＤ(％)ＳＭ３１.５０２.９９５.９８８.９８２.７７１０１.３３２.７８１００.６７３.９７９０.６４４.１３９５.９９４.３２１０２.３４７.０５９６.８２７.２２９９.６７７.４２１０２.８４１０.２５１００.００１０.０９９８.３３１０.２３９９.８９９９.１５３.４１表４㊀瑞戈非尼中基因毒性杂质检测结果批号ＳＭ２含量(％)ＳＭ３含量(％)Ｚ１９３－Ａ１９１１００１０.０００００.００１３６ＲＧＦＮ－Ｂ－１９０９０１０.０００００.００４１４３㊀讨论３.１㊀瑞戈非尼的合成工艺㊀如图１所示ꎬ以３－氟－４－氨基苯酚和Ｎ－甲基－４－氯－２－吡啶甲酰胺为原料㊁氢氧化钠为碱ꎬＴＨＦ为溶剂ꎬ回流反应得到中间体４－(４－氨基－３－氟苯氧基)－Ｎ－甲基吡啶－２－甲酰胺ꎬ该中间体再与４－氯－３－三氟甲基苯胺以羰基连接得到瑞戈非尼无水物(４－[４－[[[４－氯－３－(三氟甲基)苯基]氨基甲酰]氨基]－３－氟苯氧基]－Ｎ－甲基吡啶－２－甲酰胺)ꎬ加水而成ꎮ合成路线中涉及多个起始物料及中间体带有基因警示结构ꎬ因此ꎬ必须对瑞戈非尼合成路线中引入的带有基因警示结构的潜在基因毒性杂质进行控制ꎮ３.２㊀控制限度㊀参照瑞戈非尼片药品使用说明书ꎬ建议每日最低剂量为８０ｍｇꎬ每日最高剂量为１６０ｍｇꎮ因为瑞戈非尼为抗肿瘤用药ꎬ可以不以ＩＣＨＭ７推荐的最严格的毒理学关注阈值(ＴＴＣꎬ１.５μｇｄ－１)为控制限制ꎮ本研究基于治疗期ꎬ以相对严格的１~１０年治疗期的ＴＴＣ(１０μｇｄ－１)为控制限制计算ꎬ瑞戈非尼中基因毒性杂质限度应为６２.５ˑ１０－６ꎬ本研究以６０ˑ１０－６作为瑞戈非尼中基因毒性杂质的控制限度ꎮ本次研究用样品中未检出ＳＭ２ꎬ检出的ＳＭ３分别为１３.６ˑ１０－６㊁４１.４ˑ１０－６ꎬ均符合限度要求ꎬ但ＳＭ３检出量已超３０％限度ꎬ值得关切ꎮ３.３㊀色谱条件的优化㊀色谱条件优化试验中ꎬ探索了甲醇㊁异丙醇和乙腈３种有机相(Ｂ相)ꎬ水相(Ａ相)中添加不同比率的酸(０.１％甲酸水ꎬ０.０５％甲酸水和０.１％乙酸水)对分离度和灵敏度的影响ꎮ结果显示ꎬ采用ＡｇｉｌｅｎｔＲＲＨＤＣ１８色谱柱ꎬ当流动相０.０５％甲酸水溶液－甲醇梯度洗脱时ꎬ３－氟－４－氨基苯酚(ＳＭ２)㊁３－三氟甲基－４－氯异氰酸苯酯(ＳＭ３)响应较好ꎬ且两个化合物分离度良好ꎬ故流动相中选择０.０５％甲酸水ꎮ本试验考察了流速０.２~０.４ｍＬｍｉｎ－１范围内对苯胺类物质响应和峰形的影响ꎬ发现流速０.３ｍＬｍｉｎ－１时ꎬＳＭ２ꎬＳＭ３离子化效率最高ꎬ出峰时间合适ꎬ且峰形较好ꎮ３.４㊀质谱解析㊀３－氟－４－氨基苯酚的质谱图中ｍ/ｚ１２８.０５为[Ｍ＋Ｈ]＋离子ꎬ主要的碎片离子有ｍ/ｚ１０８和ｍ/ｚ８１.１ꎬ其中ｍ/ｚ１０８为去氟基产物ꎬ反映了３－氟－４－氨基苯酚的结构特征ꎮ试验对３－氟－４－氨基苯酚２个离子对ｍ/ｚ１２８.０５ң１０８和ｍ/ｚ１２８.０５ң８１.１的ＭＲＭ参数见表１ꎬ其中ꎬ离子对ｍ/ｚ１２８.０５ң１０８的信噪比较离子对ｍ/ｚ１２８.０５ң８１.１更高ꎬ因此选择ｍ/ｚ１２８.０５ң１０８作为定量离子对ꎬｍ/ｚ１２８.０５ң８１.１作为定性离子对ꎮ本法中ＳＭ３检测采用异丙醇衍生化ꎬ分析对象为ＳＭ３与异丙醇衍生后的产物ꎮ衍生产物精确分子量为２８１.０４ꎬ其[Ｍ－Ｈ]－为２８０ꎬ反应过程见图５ꎮ图５㊀ＳＭ３衍生化反应(下转第５２５页)ｆａｔｔｙａｃｉｄｂｉｏｇｅｎｅｓｉｓ:ａｎｅｗｆａｍｉｌｙｏｆａｎｔｉ－ｃａｎｃｅｒａｇｅｎｔｓ?[Ｊ].ＣｕｒｒＰｈａｒｍＢｉｏｔｅｃｈｎｏｌꎬ２００６ꎬ７(６):４８３－４９３.[８７]ＣＨＥＮＸꎬＨＵＡＮＧＫꎬＨＵＳꎬｅｔａｌ.ＦＡＳＮ－ＭｅｄｉａｔｅｄＬｉｐｉｄＭｅｔａｂｏｌｉｓｍＲｅｇｕｌａｔｅｓＧｏｏｓｅＧｒａｎｕｌｏｓａＣｅｌｌｓＡｐｏｐｔｏｓｉｓａｎｄＳｔｅｒｏｉｄｏｇｅｎｅｓｉｓ[Ｊ].ＦｒｏｎｔｉｎＰｈｙｓｉｏｌꎬ２０２０(１１):６００.[８８]ＣＨＯＹＫꎬＳＯＮＹꎬＫＩＭＳＮꎬｅｔａｌ.ＭｉｃｒｏＲＮＡ－１０ａ－５ｐｒｅｇｕｌａｔｅｓｍａｃｒｏｐｈａｇｅｐｏｌａｒｉｚａｔｉｏｎａｎｄｐｒｏｍｏｔｅｓｔｈｅｒａｐｅｕｔｉｃａｄｉｐｏｓｅｔｉｓｓｕｅｒｅｍｏｄｅｌｉｎｇ[Ｊ].ＭｏｌＭｅｔａｂꎬ２０１９(２９):８６－９８.[８９]ＸＵＥＭꎬＹＡＮＧＭｘｉｎｇꎬＺＨＡＮＧＷꎬｅｔａｌ.Ｃｈａｒａｃｔｅｒｉｚａｔｉｏｎꎬｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓꎬａｎｄｈｙｐｏｇｌｙｃｅｍｉｃｅｆｆｅｃｔｏｆｂｅｒｂｅｒｉｎｅｌｏａｄｅｄｓｏｌｉｄｌｉｐｉｄｎａｎｏｐａｒｔｉｃｌｅｓ[Ｊ].ＩｎｔＪＮａｎｏｍｅｄｉｃｉｎｅꎬ２０１３(８):４６７７－４６８７.[９０]ＸＵＥＭꎬＺＨＡＮＧＬꎬＹＡＮＧＭＸꎬｅｔａｌ.Ｂｅｒｂｅｒｉｎｅ－ｌｏａｄｅｄｓｏｌｉｄｌｉｐｉｄｎａｎｏｐａｒｔｉｃｌｅｓａｒｅｃｏｎｃｅｎｔｒａｔｅｄｉｎｔｈｅｌｉｖｅｒａｎｄａｍｅｌｉｏｒａｔｅｈｅｐａｔｏｓｔｅａｔｏｓｉｓｉｎｄｂ/ｄｂｍｉｃｅ[Ｊ].ＩｎｔＪＮａｎｏ￣ｍｅｄｉｃｉｎｅꎬ２０１５(１０):５０４９－５０５７.[９１]ＺＨＡＯＪꎬＺＨＡＯＱꎬＬＵＪＺꎬｅｔａｌ.ＮａｔｕｒａｌＮａｎｏ－ＤｒｕｇＤｅ￣ｌｉｖｅｒｙＳｙｓｔｅｍｉｎＣｏｐｔｉｄｉｓＲｈｉｚｏｍａＥｘｔｒａｃｔｗｉｔｈＭｏｄｉｆｉｅｄＢｅｒｂｅｒｉｎｅＨｙｄｒｏｃｈｌｏｒｉｄｅＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓ[Ｊ].ＩｎｔＪＮａｎｏｍｅｄｉｃｉｎｅꎬ２０２１(１６):６２９７－６３１１.[９２]ＤＵＯＮＧＴＴꎬＩＳＯＭÄＫＩＡꎬＰＡＡＶＥＲＵꎬｅｔａｌ.Ｎａｎｏｆｏｒｍｕ￣ｌａｔｉｏｎａｎｄＥｖａｌｕａｔｉｏｎｏｆＯｒａｌＢｅｒｂｅｒｉｎｅ－ＬｏａｄｅｄＬｉｐｏｓｏｍｅｓ[Ｊ].Ｍｏｌｅｃｕｌｅｓꎬ２０２１ꎬ２６(９):２５９１.[９３]ＳＡＨＩＢＺＡＤＡＭＵＫꎬＺＡＨＯＯＲＭꎬＳＡＤＩＱＡꎬｅｔａｌ.Ｂｉｏ￣ａｖａｉｌａｂｉｌｉｔｙａｎｄｈｅｐａｔｏｐｒｏｔｅｃｔｉｏｎｅｎｈａｎｃｅｍｅｎｔｏｆｂｅｒｂｅｒｉｎｅａｎｄｉｔｓｎａｎｏｐａｒｔｉｃｌｅｓｐｒｅｐａｒｅｄｂｙｌｉｑｕｉｄａｎｔｉｓｏｌ￣ｖｅｎｔｍｅｔｈｏｄ[Ｊ].ＳａｕｄｉＪＢｉｏｌＳｃｉꎬ２０２１ꎬ２８(１):３２７－３３２.[９４]ＣＨＯＷＹＬꎬＳＯＧＡＭＥＭꎬＳＡＴＯＦ.１３－Ｍｅｔｈｙｌｂｅｒｂｅｒｉｎｅꎬａｂｅｒｂｅｒｉｎｅａｎａｌｏｇｕｅｗｉｔｈｓｔｒｏｎｇｅｒａｎｔｉ－ａｄｉｐｏｇｅｎｉｃｅｆｆｅｃｔｓｏｎｍｏｕｓｅ３Ｔ３－Ｌ１ｃｅｌｌｓ[Ｊ].ＳｃｉｅｎｔｉｆｉｃＲｅｐｏｒｔｓꎬ２０１６ꎬ６(１):３８１２９.[９５]ＲＥＢＥＬＬＯＣＪꎬＧＲＥＥＮＷＡＹＦＬ.Ｏｂｅｓｉｔｙｍｅｄｉｃａｔｉｏｎｓｉｎｄｅｖｅｌｏｐｍｅｎｔ[Ｊ].ＥｘｐｅｒｔＯｐｉｎＩｎｖｅｓｔｉｇＤｒｕｇｓꎬ２０２０ꎬ２９(１):６３－７１.(收稿日期:２０２２－１２－３１)(上接第４８８页)㊀㊀ＳＭ３衍生产物ꎬ在质谱离子源中ꎬ子离子为酯键断裂后重排的ｍ/ｚꎬ碎裂途径见图６ꎮ图６㊀ＳＭ３子离子裂解途径本研究建立了超高效液相色谱－串联质谱法测定瑞戈非尼中的２种基因毒性杂质(３－氟－４－氨基苯酚(ＳＭ２)㊁３－三氟甲基－４－氯异氰酸苯酯(ＳＭ３)ꎬ并进行了方法学验证ꎬ可以有效控制瑞戈非尼的潜在基因毒性杂质ꎮ该方法专属性强ꎬ灵敏度高ꎬ满足基因毒性杂质测定要求ꎬ可以作为瑞戈非尼原料药中基因毒性杂质的质控方法ꎮ参考文献:[１]㊀ＥｕｒｏｐｅａｎＭｅｄｉｃｉｎｅｓＡｇｅｎｃｙ(ＥＭＡ).ＧｕｉｄｅｌｉｎｅｏｎｔｈｅＬｉｍｉｔｓｏｆＧｅｎｏｔｏｘｉｃＩｍｐｕｒｉｔｉｅｓ(欧洲药品管理局关于基因毒性杂质限度指导原则)[ＥＢ/ＯＬ].[２０１５－０３－０２].ｈｔｔｐ://ｗｗｗ.Ｅｍａ.Ｅｕｒｏｐａ.ｅｕ/ｄｏｃｓ/ｅｎ＿ＧＢ/ｄｏｃｕｍｅｎｔ＿ｌｉ￣ｂｒａｒｙ/Ｓｃｉｅｎｔｉｆｉｃ＿ｇｕｉｄｅｌｉｎｅ/２００９/０９/ＷＣ５００００２９０３.ｐｄｆ.[２]ＥｕｒｏｐｅａｎＭｅｄｉｃｉｎｅｓＡｇｅｎｃｙ(ＥＭＡ).ＱｕｅｓｔｉｏｎｓａｎｄＡｎｓｗｅｒｓｏｎｔｈｅＧｕｉｄｅｌｉｎｅｏｎｔｈｅＬｉｍｉｔｓｏｆＧｅｎｏｔｏｘｉｃＩｍ￣ｐｕｒｉｔｉｅｓ[ＥＢ/ＯＬ].(２０１０－０９－２３)[２０１５－０３－０２].ｈｔｔｐ//ｗｗｗ.ｅｍａ.ｅｕｒｏｐａ.ｅｕ/ｄｏｃｓ/ｅｎ＿ＧＢ/ｄｏｃｕｍｅｎｔ＿ｌｉｂｒａｒｙ/Ｓｃｉ￣ｅｎｔｉｆｉｃ＿ｇｕｉｄｅｌｉｎｅ/２００９/０９/ＷＣ５００００２９０７.ｐｄｆ.[３]ＦｏｏｄａｎｄＤｒｕｇＡｄｍｉｎｉｓｔｒａｔｉｏｎ(ＦＤＡ).ＧｅｎｏｔｏｘｉｃａｎｄＣａｒ￣ｃｉｎｏｇｅｎｉｃＩｍｐｕｒｉｔｉｅｓＩｎＤｒｕｇＳｕｂｓｔａｎｃｅｓａｎｄＰｒｏｄｕｃｔｓ:ＲｅｃｏｍｍｅｎｄｅｄＡｐｐｒｏａｃｈｅｓ.[２０１５－０８－２６].[４]ＩｎｔｅｒｎａｔｉｏｎａｌＣｏｎｆｅｒｅｎｃｅｏｎＨａｒｍｏｎｉｚａｔｉｏｎｏｆＴｅｃｈｎｉｃａｌＲｅｑｕｉｒｅｍｅｎｔｓｆｏｒＲｅｇｉｓｔｒａｔｉｏｎｏｆＰｈａｒｍａｃｅｕｔｉｃａｌｓｆｏｒＨｕ￣ｍａｎＵｓｅ(ＩＣＨ).ＡｓｓｅｓｓｍｅｎｔａｎｄＣｏｎｔｒｏｌｏｆＤＮＡＲｅａｃｔｉｖｅ(Ｍｕｔａｇｅｎｉｃ)ＩｍｐｕｒｉｔｉｅｓｉｎＰｈａｒｍａｃｅｕｔｉｃａｌｓｔｏＬｉｍｉｔＰｏ￣ｔｅｎｔｉａｌＣａｒｃｉｎｏｇｅｎｉｃＲｉｓｋＭ７(Ｒ１).[２０１５－０８－２６].[５]ＲＡＭＡＮＮＶＶＳＳꎬＰＲＡＳＡＤＡＶＳＳꎬＲＥＤＤＹＫＲ.Ｓｔｒａｔｅｇｉｅｓｆｏｒｔｈｅｉｄｅｎｔｉｆｉｃａｔｉｏｎꎬｃｏｎｔｒｏｌａｎｄｄｅｔｅｒｍｉｎａｔｉｏｎｏｆｇｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｉｅｓｉｎｄｒｕｇｓｕｂｓｔａｎｃｅｓ:ａｐｈａｒｍａｃｅｕｔｉｃａｌｉｎｄｕｓｔｒｙｐｅｒｓｐｅｃｔｉｖｅｓ[Ｊ].ＪＰｈａｒｍＢｉｏｍｅｄＡｎａｌꎬ２０１１ꎬ５５(４):６６２－６６７.[６]ＳＺＥＫＥＬＹＧꎬＡＭＯＲＥＳＤＥＳＯＵＳＡＭＣꎬＧＩＬＭꎬｅｔａｌ.ＧｅｎｏｔｏｘｉｃＩｍｐｕｒｉｔｉｅｓｉｎＰｈａｒｍａｃｅｕｔｉｃａｌＭａｎｕｆａｃｔｕｒｉｎｇ:ＳｏｕｒｃｅｓꎬＲｅｇｕｌａｔｉｏｎｓꎬａｎｄＭｉｔｉｇａｔｉｏｎ[Ｊ].ＣｈｅｍｉｃａｌＲｅｖｉｅｗｓꎬ２０１５ꎬ１１５(１６):８１８２－８２２９.[７]甘勇军ꎬ王以武ꎬ张量ꎬ等.瑞戈非尼的合成工艺优化[Ｊ].中国医药工业杂志ꎬ２０２０ꎬ５１(２):１９６－１９９.[８]曹琳ꎬ罗淑青ꎬ章燕ꎬ等.ＬＣ－ＱＱＱ－ＭＳ/ＭＳ分析苯磺酸氨氯地平中痕量苯磺酸酯类基因毒性杂质[Ｊ].中国现代应用药学ꎬ２０２０ꎬ３７(１１):１２９６－１３００.[９]芦飞ꎬ邢珊珊ꎬ王咏.ＬＣ－ＭＳ测定醋酸甲羟孕酮中对甲苯磺酸甲酯及对甲苯磺酸乙酯的含量[Ｊ].中国现代应用药学ꎬ２０１８ꎬ３５(５):６５７－６５９.(收稿日期:２０２３－０２－２４)。

阿司咪唑

合成方法
合成方法
化合物(I)和碘甲烷在乙醇中回流8h，环合得到化合物(Ⅱ)。再水解脱去酯基，得到化合物(Ⅲ)。用对甲氧基苯乙基溴进行N-烷基化，得化合物(Ⅳ)。再用对氟苄基溴烷基化，得阿司咪唑。
1. 1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮的制备
在反应瓶中加入2-羟基苯并咪唑5.0g(37.3mmol)和NaH 1.6g(53mmol)(NaH含量大约为80%,浸入矿物油中) 的DMF 100ml的悬浮液.加毕.在60ºC.(最好有N2保护)搅拌反应1h.再加入4-氟苄基氯(FBC)5.4g(37mmol),加热 ( 6 0 ºC ) 搅拌反应 5 . 5 h . 冷却至室温后加入冰水 7 0 0 m l , 用二氯甲烷 ( 5 0 0 m l × 2 ) 提取 . 有机层用食盐水洗 . 无水 N a 2 S O 4 干燥.过滤.滤液减压浓缩.剩余物用石油醚析晶.得1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮固体8.0g,为无色结晶 m p 1 7 8 ~ 1 7 9 ºC , 收率 8 8 % .
治疗措施
阿司咪唑中毒的治疗要点为： 1.大量摄入者予洗胃，后灌服活性炭和导泻。 2.对心肌抑制和Q-T间期延长者予5%碳酸氢钠250ml静注可能有效。 3.对症、支持治疗。
专家点评
专家点评
阿司咪阿司咪唑自1983年上市以来，在许多国家得到了广泛应用。国外研究显示阿司咪唑治疗荨麻疹的总有效率为74%。国内的一项多中心双盲安慰剂对照试验表明阿司咪唑对急性荨麻疹的总有效率为82.9%，对慢性荨麻疹的总有效率为86.0%，均显著高于安慰剂，主要不良反应为嗜睡、倦怠、口干等，连续用药3个月的患者中，半数有食欲及体重增加。阿司咪唑的心脏毒性虽然发生率较低，但由于后果严重，已限制了它的应用。阿司咪唑为强效和长效的H1受体拮抗剂，无中枢镇静和抗毒蕈碱样作用。代谢产物去甲阿司咪唑仍有抗胆胺作用。长期服用可增进食欲和增加体重，服用过量可引起心脏Q-T间期延长和室性心律失常。适用于各种原因引起过敏性疾病。

GC测定盐酸普拉克索中三乙胺残留量

ABSTRACT: OBJECTIVE To determine the triethylamine in pramipexole hydrochloride by GC. METHODS The residual triethylamine was determined by HS-GC with Agilent-INNOWAX capillary column(30 m×0.32 mm, 0.5 μm) and FID detector. The carrier gas was nitrogen and the flow rate was 4.0 mL·min1. The temperature of the injection port was maintaining at 250 ℃ and the same of detector. The oven introduced sequential increasing of temperature programing. The initial column temperature was 50 ℃, then raised the temperature to 150℃ at a rate of 10 ℃·min1, and maintained it at 150 ℃ for 5 min, then raised the temperature to 220 ℃ at a rate of 40 ℃·min1, and maintained it for 5 min. The headspace oven was set at a temperature of 80 ℃ for 30 min. The solvent was 20% sodium hydroxide solution. The triethylamine was quantified external standard. RESULTS The calibration shows a good linearity with the range of 0.31712.68 μg·mL1 for triethylamine. The average recovery was 97.9%(n=9). The precision was 4.18%(n=9). CONCLUSION This method is accurate, reliable and sensitive for the

ICHM7(step4)基因毒性杂质评估和控制◆中英

ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT POTENTIAL CARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制M7Current Step 4 versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.M7Document History 文件历史The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document.The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制ICH Harmonised Tripartite GuidelineICH三方协调指南Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制1. INTRODUCTION概述The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals (Ref. 3).原料药合成牵涉到使用活性化学物质、试剂、溶剂、催化剂和其它工艺助剂，导致在所有原料药及其制剂中会残留有化学合成或其降解产物、杂质。

ICHM7(step4)基因毒性杂质评估和控制◆中英

Keap1

非小细胞肺癌(non-small cell lung cancer，NSCLC)发病率占据肺癌的75%~80%。

肿瘤细胞进展快且易扩散转移，临床常采用手术、放化疗等进行治疗，但5年生存率低于60%[1-2]。

氧化应激是由活性氧(ROS)生成量增加所致，ROS积累可诱导肺癌细胞凋亡，清除ROS 可阻止癌细胞凋亡，即肺癌细胞存活依赖于癌细胞自身抗氧化能力[3]。

Kelch样环氧氯丙烷相关蛋白-1 (kelch-like epichlorohydrin-associated protein-1，Keap1)/核因子E2相关因子2(nuclear factor E2related factor 2，Nrf2)信号通路在癌症中发挥重要调控作用，氧化应激可激活Keap1，促使Keap1-Nrf2复合物裂解，Nrf2转移至细胞核内，可激活下游靶基因表达，参与肺癌发生发展过程[4]。

Nrf2可维持氧化还原稳态，ROS侵袭细胞时，Nrf2可进入细胞核，结合抗氧化反应元件(ARE)转录编码各种抗氧化蛋白、代谢酶基因，抑制氧化应激反应[5-6]。

目前氧化应激、Keap1/Nrf2信号通路在NSCLC发生过程中的机制尚未明确。

基于此，本研究尝试分析Keap1/Nrf2信号通路与临床病理参数、氧化应激指标的相关性，探讨其在NSCLC氧化应激机制中的作用，为临床研制新药提供参考依据。

1资料与方法1.1一般资料选取2017年4月至2020年4月郑州市第三人民医院收治的100例NSCLC患者为研究对象。

纳入标准：符合NSCLC诊断标准[7]；术前未接受放化疗、免疫治疗者；预计生存期≥6个月；符合手术适应证、禁忌证；Karnofsky功能状态评分≥70分；签署知情同意书。

排除标准：合并凝血功能障碍、肝肾功能障碍、其他恶性肿瘤者；伴有急/慢性感染者；伴有精神疾病者；既往腹部相关外科手术史者。

所有患者均行肺癌根治性切除术，术中收集癌组织、癌旁组织(距离癌组织5cm范围内正常组织)，其中男性63例，女性37例；年龄46~67岁，平均(56.32±3.16)岁；体质量指数(BMI)17~30kg/m2，平均(23.16±2.03)kg/m2；病理类型：鳞癌58例、腺癌42例；病理分级[8]：Ⅰ~Ⅱ级51例、Ⅲ级49例；T分期[9]：T1~T253例、T3~T447例；N分期：N055例、N1~N245例。

致敏染料致癌染料测试

OTC国际认证技术中心，欢迎前来咨询！欧洲CE认证尼日利亚SONCAP 沙特SASO 肯尼亚PVOC 坦桑尼亚COC 阿尔及利亚COC 赞比亚PVOC 墨西哥NOM 乌拉圭LATU 印度BIS 国际体育澳标AS 美标ASTM致敏染料/致癌染料测试：Allergenous disperse dyes 致敏性分散染料 HPLC-MS , DIN 54231Carcinogen dyes 致癌染料 HPLC-MS , DIN 54231常见含有致敏染料产品- 聚酯纤维、聚酰胺纤维及醋酸纤维的染色处理- 由于分散染料的分子量很低，经常用于涤纶转移印花- 色牢度比较差的尼龙织物- 目前容易出现致敏染料超标的产品有：? 长筒袜? 护腿? 短袜? 紧身衣? 罩衫和内衣一、致敏性分散染料Allergenous disperse致敏染料是指某些会引起人体或动物的皮肤、黏膜或呼吸道过敏的染料。

人体吸入性的过敏主要集中于呼吸道和粘膜，部分活性染料（可分为颗粒状和液状）可造成此类致敏。

目前致敏染料共发现27种。

在国际知名生态安全规范Oeko-Tex Standard 100的2008版中，将其中的20种致敏性分散染料列为生态纺织品的监控项目，下表中1#~20#，并增加了另外两种致敏染料，21#和22#。

这些染料主要用于聚酯、聚酰胺和醋酯纤维的染色，其中的17种为早期用于醋酸纤维的分散染料。

欧盟于2002年5月推出的Eco-Label标签标准规定：该标准所列出的17种染料（比Oeko-Tex Standard 100少了3种：C.I. 分散蓝1、C.I. 分散棕1和C.I. 分散黄3），并规定当染色纺织品的耐汗渍色牢度（酸性和碱性）低于4级时，不得使用。

禁用的致敏染料编号染料英文名称染料中文名称 CAS No.1#Disperse Blue 1 分散蓝1 2475-45-82# Disperse Blue 3 分散蓝3 2475-46-93# Disperse Blue 7 分散蓝7 3179-90-64# Disperse Blue 26 分散蓝26 3860-63-75# Disperse Blue 35 分散蓝35 12222-75-26# Disperse Blue 102 分散蓝102 69766-79-67# Disperse Blue 106 分散蓝106 12223-01-78# Disperse Blue 124 分散蓝124 61951-51-79# Disperse Brown 1 分散棕1 23355-64-810# Disperse Orange 1 分散橙 1 2581-69-311# Disperse Orange 3 分散橙3 730-40-512# Disperse Orange 37/76 分散橙37/76 13301-61-613# Disperse Red 1 分散红1 2872-52-814# Disperse Red 11 分散红11 2872-48-215# Disperse Red 17 分散红17 3179-89-316# Disperse Yellow 1 分散黄1 119-15-317# Disperse Yellow 3 分散黄3 2832-40-818# Disperse Yellow 9 分散黄 9 6373-73-519# Disperse Yellow 39 分散黄39 12236-29-220# Disperse Yellow 49 分散黄49 54824-37-221# Disperse Yellow 23 分散黄23 6250-23-322# Disperse Orange 149 分散橙149 85136-74- 9国际上目前对纺织品上限用致敏性分散染料检出的限定值，不同的买家所制订的合格性评定标准存在一些差异。

单过氧马来酸叔丁酯[糊状物]安全技术说明书msds

第十五部分法规信息
《危险化学品目录（2015 年版）》，安监总局 2015 年第 5 号公告
第十六部分其它信息
参考文献
【1】国际化学品安全规划署：国际化学品安全卡（ICSCs）
【2】国际癌症研究机构
【3】OECD 全球化学品信息平台
【4】美国 CAMEO 化学物质数据库
【5】美国医学图书馆:化学品标识数据库
第九部分：理化特性
外观与性状：
白色粘性糊状物
pH值（指明浓度）：
无资料
气味：
无资料
沸点、初沸点和沸程(℃)：
>35
熔点/凝固点(℃)：
无资料
相对蒸气密度(空气=1)：
无资料
气味临界值：
无资料
饱和蒸气压(kPa)：
无资料
相对密度(水=1)：
无资料
蒸发速率：
无资料
黏度(mm2/s)：
无资料
闪点 (℃)：
无资料
分解产物：
在正常的储存和使用条件下，不会产生危险的分解产物。
第十一部分毒理学资料
急性毒性：
LD50(经口)：无资料
LD50(经皮)：无资料
LC50(吸入)：无资料
致癌性：
未列入
皮肤刺激性或腐蚀性：
无资料
眼睛刺激或腐蚀：
无资料
皮肤致敏：
无资料
呼吸致敏：
无资料
生殖细胞突变性：
无资料
生殖毒性：
无资料
无资料
n-辛醇/水分配系数：
无资料
分解温度(℃)：
无资料
引燃温度(℃)：
无资料
爆炸上限 [％(V/V)]：
无资料
爆炸下限[％(V/V)]：

BAM7_331244-89-4_MSDS_MedChemExpress

四苯基乙烯衍生物的合成与生物成像研究

BAM7_SDS_MedChemExpress

分子生物学词汇(中英文对照表 )

Gelucire-14-44-SDS-MedChemExpress

四丁基氢氧化铵化学品安全技术说明书

玛巴洛沙韦 结构式

封闭添加试剂(按字母顺序排列)

7-(乙基氨基)-4-甲基香豆素

UHPLC－MS

阿司咪唑

GC测定盐酸普拉克索中三乙胺残留量

ICHM7(step4)基因毒性杂质评估和控制◆中英

ICHM7(step4)基因毒性杂质评估和控制◆中英

Keap1

致敏染料致癌染料测试

单过氧马来酸叔丁酯[糊状物]安全技术说明书msds

玛巴洛沙韦结构式