staurosporine | 62996-74-1

• 物质功能分类: 原料药 - 抗生素类药物 - 其它抗生素类药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: staurosporine
• 英文别名: staurasporine；STU；Staurosporine HCl；3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one
• CAS: 62996-74-1
• 化学式: C₂₈H₂₆N₄O₃
• 分子量: 466.539
• InChiKey: HKSZLNNOFSGOKW-UHFFFAOYSA-N

物化性质

• 熔点：
  270°C
• 比旋光度：
  D25 +35.0° (c = 1 in methanol); D22 +56.1° (c = 0.14 in methanol)
• 沸点：
  677.5±55.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  35
• 可旋转键数：
  2
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  69.4
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险等级：
  3
• 危险品标志：
  Xn,Xi,T
• 安全说明：
  S36,S37,S53
• 危险类别码：
  R40
• WGK Germany：
  2
• 海关编码：
  29419090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  存储条件：0-10°C，需置于惰性气体中，避免与空气接触及加热。

SDS

Name:	Staurosporine Material Safety Data Sheet
Synonym:	Antibiotic AM-228
CAS:	62996-74-1

Section 1 - Chemical Product MSDS Name:Staurosporine Material Safety Data Sheet
Synonym:Antibiotic AM-228

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
62996-74-1	Staurosporine	ca 100	unlisted

Hazard Symbols: XN
Risk Phrases: 40

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Limited evidence of a carcinogenic effect.Light sensitive.Moisture sensitive.The toxicological properties of this material have not been fully investigated.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
May cause irritation of the digestive tract. The toxicological properties of this substance have not been fully investigated.
Inhalation:
May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated.
Chronic:
No information found.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
Never give anything by mouth to an unconscious person. Get medical aid. Do NOT induce vomiting. If conscious and alert, rinse mouth and drink 2-4 cupfuls of milk or water. Wash mouth out with water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion.
Non-combustible, substance itself does not burn but may decompose upon heating to produce irritating, corrosive and/or toxic fumes.
Extinguishing Media:
Substance is noncombustible; use agent most appropriate to extinguish surrounding fire. Do NOT get water inside containers. Use water spray, dry chemical, carbon dioxide, or appropriate foam.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container. Clean up spills immediately, observing precautions in the Protective Equipment section. Avoid generating dusty conditions.
Provide ventilation. Do not get water inside containers.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Use with adequate ventilation.
Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation. Store protected from light. Do not allow contact with water. Keep from contact with moist air and steam.
Storage:
Do not store in direct sunlight. Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances. Keep refrigerated. (Store below 4C/39F.) Store protected from moisture. Store protected from light.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Facilities storing or utilizing this material should be equipped with an eyewash facility and a safety shower. Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 62996-74-1: Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
A respiratory protection program that meets OSHA's 29 CFR 1910.134 and ANSI Z88.2 requirements or European Standard EN 149 must be followed whenever workplace conditions warrant respirator use.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Powder
Color: off-white
Odor: none reported
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 270 deg C
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water:
Specific Gravity/Density:
Molecular Formula: C28H26N4O3
Molecular Weight: 466.207

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable at room temperature in closed containers under normal storage and handling conditions.
Conditions to Avoid:
Incompatible materials, light, moisture, excess heat, exposure to moist air or water.
Incompatibilities with Other Materials:
Moisture, strong oxidizing agents.
Hazardous Decomposition Products:
Hydrogen chloride, nitrogen oxides, carbon monoxide, irritating and toxic fumes and gases, carbon dioxide.
Hazardous Polymerization: Will not occur.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 62996-74-1: KC6550000 LD50/LC50:
Not available.
Carcinogenicity:
Staurosporine - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
No information available.
IMO
No information available.
RID/ADR
No information available.

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: XN
Risk Phrases:
R 40 Limited evidence of a carcinogenic effect.
Safety Phrases:
S 28A After contact with skin, wash immediately with
plenty of water.
S 36/37 Wear suitable protective clothing and
gloves.
S 37 Wear suitable gloves.
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 62996-74-1: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 62996-74-1 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 62996-74-1 is not listed on the TSCA inventory.
It is for research and development use only.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

概述

斯塔尿丁（Staurosporine）具有广泛的生物活性，从抗真菌到抗高血压。这些多样的生物活性引起了广泛的研究兴趣，并促成了抗癌治疗潜力的发现。其主要的生物活性是通过预防ATP与激酶结合来抑制蛋白激酶。具体而言，斯塔尿丁对激酶上的ATP结合位点具有更强的亲和力。

应用

作为一种典型的ATP竞争性激酶抑制剂，斯塔尿丁能够以高亲和力结合多种激酶，但选择性很低。激酶袋结构分析表明，在与斯塔尿丁相对位置保守的主要链原子有助于其杂乱分布。

结构特性

斯塔尿丁（staurosporine, sta）是一种天然产物，具有较好的药理学和生物活性。该化合物于1997年由Omura首次从土壤放线菌中分离得到，并被证明为强PKC抑制剂（IC50＝2.7 nM），主要作用于细胞信号转导通路中的各种激酶、拓扑异构酶以及细胞周期调控因子。

生产与提取

斯塔尿丁是米哚妥林的关键中间体，其生产工艺直接影响生产成本和质量。提取方法包括发酵完成后，将培养基pH值调整至10，并用正丁酸乙酯进行提取；加入盐酸水溶液后，产品转移到水相中；再调节pH值至10并使用乙酸乙酯萃取，浓缩得到褐色凝胶状物质；最后通过乙醚洗涤去除脂肪，并利用硅胶层析分离。洗脱剂为氯仿-甲醇混合液，并采用薄层层析进行控制、浓缩和干燥后即可获得纯品，其纯度高达99%以上。

生物活性

斯塔尿丁是一种有效的PKC抑制剂，在无细胞试验中对PKCα、γ和η具有高度选择性（IC50分别为2 nM、5 nM 和 4 nM），但对PKCδ和ε的作用较弱，分别表现为20 nM和73 nM；同时对其他激酶如PKA、PKG、S6K、CaMKII等也显示出抑制活性。它在体外研究中还能够诱导HeLa S3细胞凋亡（IC50为4 nM），并对多种蛋白激酶具有抑制作用，包括但不限于PKA、磷酸激酶、S6激酶和肌球蛋白轻链激酶（MLCK）等。

靶点

• PKCα：2 nM
• c-Fgr：2 nM
• 磷酸化酶激酶：3 nM
• PKCη：4 nM
• PKCγ：5 nM

体外研究

斯塔尿丁在无细胞试验中表现出对HeLa S3细胞的强大抑制作用，IC50为4 nM。它还抑制了多种其他蛋白激酶如PKA、PKG等，并诱导PC12细胞90%以上的凋亡；这种效应可通过过表达Bcl-2、zVAD-fmk或使用cycloheximide和actinomycin D处理而被部分或完全抑制。此外，斯塔尿丁还能激活传统线粒体凋亡通路和一种新型内在凋亡通路。

体内研究

在局部缺血模型中，用斯塔尿丁（0.1-10 ng）预处理可防止神经元损伤，这表明PKC参与了CA锥体细胞的死亡过程。

反应信息

• 作为反应物：
  描述：

  staurosporine 在 哌啶 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成
  参考文献：
  名称：

  SELECTIVE INHIBITORS FOR PROTEIN KINASES AND PHARMACEUTICAL COMPOSITION AND USE THEREOF

  摘要：

  本发明提供了式（I）的化合物或其盐：其中R至少选择自未取代的C1-4烷基，被C6-18芳基或-OR1取代的C1-4烷基，和-C（═O）Z。该化合物是一种类型S蛋白激酶抑制剂，可以同时结合蛋白激酶的ATP结合位点和底物识别位点。本发明还提供了一种制药组合物，包括式（I）的化合物或其盐和其药学上可接受的载体。本发明还提供了一种使用式（I）的化合物或其盐的方法，用于制造蛋白激酶抑制剂作为药物。

  公开号：

  US20160096848A1

文献信息

• Staurosporine derivatives substituted at methylamino nitrogen
  申请人：Ciba-Geigy Corporation

  公开号：US05093330A1

  公开（公告）日：1992-03-03

  N-substituted derivatives of staurosporine of the general formula [Stau]--N(CH.sub.3)--R (I) in which [Stau] represents a residue of the partial formula ##STR1## and R represents a hydrocarbyl radical R.sup.o or an acyl radical Ac, which radicals preferably have a maximum of 30 carbon atoms, and salts of compounds of the formula I having salt-forming properties, are distinguished as selective inhibitors of proteinkinase C. They are manufactured by conventional alkylation or acylation, respectively, of staurosporine.

  通式为[Stau]--N(CH.sub.3)--R (I)的Staurosporine的N-取代衍生物中，[Stau]代表部分式的残基##STR1##，R代表烃基R.sup.o或酰基Ac，这些基团最好具有最多30个碳原子，并且具有盐形成性质的公式I的化合物的盐，被称为蛋白激酶C的选择性抑制剂。它们是通过常规的staurosporine烷基化或酰化制造的。
• Crystal form of N-benzoyl-staurosporine
  申请人：Novartis AG

  公开号：US08198435B2

  公开（公告）日：2012-06-12

  The invention relates to a new crystalline form II of N-benzoyl-staurosporine; compositions containing the same; processes for the preparation thereof; and the use of crystalline form II of N-benzoyl-staurosporine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans. The invention relates to the amorphous forms of N-benzoyl-staurosporine; compositions containing the same; processes for the preparation thereof; and the use of amorphous N-benzoyl-staurosporine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.

  本发明涉及N-苯甲酰-链霉菌素的新晶体形式II，包含该晶体形式的组合物，其制备方法，以及在诊断方法或治疗温血动物，特别是人类中使用晶体形式II的N-苯甲酰-链霉菌素。本发明还涉及N-苯甲酰-链霉菌素的非晶态形式，包含该非晶态形式的组合物，其制备方法，以及在诊断方法或治疗温血动物，特别是人类中使用非晶态N-苯甲酰-链霉菌素。
• STAUROSPORIN DERIVATIVES
  申请人：KYOWA HAKKO KOGYO CO., LTD.

  公开号：EP0383919A1

  公开（公告）日：1990-08-29

  Novel staurosporin derivatives represented by formula (I) (wherein R1 represents hydrogen, lower alkyl, formyl or amino, R2 represents hydrogen, formyl, lower alkanoyl or a group formed by removing a hydroxy moiety from the carboxyl group of an a-amino acid whose amino group may optionally be protected, one of X1 and X2 represents hydrogen and the other represents hydrogen, hydroxy, lower alkoxy or lower alkylthio, or X' and X2 are taken together to form oxygen, provided that, when R1 and R2 are both hydrogen atoms and one of X1 and X2 is hydrogen, the other represents a group other than hydrogen or hydroxy) and their pharmacologically acceptable salts are disclosed. These compounds inhibit protein kinase C and have a cell growth inhibiting activity.

  本发明涉及一种以式(I)表示的新型链霉亲菌素衍生物（其中R1代表氢、低碳基、甲酰基或氨基，R2代表氢、甲酰基、低碳酰基或者是由去除α-氨基酸羧基的羟基部分而形成的基团，该α-氨基酸羧基的氨基部分可以选择性地被保护，X1和X2中的一个代表氢，另一个代表氢、羟基、低碳基氧或低碳基硫，或者X'和X2结合形成氧，但当R1和R2均为氢原子且X1和X2中的一个为氢时，另一个代表的是除氢或羟基以外的基团），以及其药学上可接受的盐。这些化合物能够抑制蛋白激酶C并具有细胞生长抑制活性。
• WO2006048296A1
  申请人：——

  公开号：——

  公开（公告）日：——
• An Methylamino-Stickstoff substituierte Derivate von Staurosporin
  申请人：CIBA-GEIGY AG

  公开号：EP0296110B1

  公开（公告）日：1996-02-21