RACGTPASE抑制剂(EHOP-016) | 1380432-32-5

• 物质功能分类: 生物化工 - 抑制剂 - 细胞周期(Cell Cycle)
• 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
• 中文名称: RACGTPASE抑制剂(EHOP-016)
• 中文别名: N4-（9-乙基-9H-咔唑-3-基）-N2-[3-（4-吗啉基）丙基]-2,4-嘧啶二胺;RACGTPASE抑制剂（EHOP-016）；N4-（9-乙基-9H-咔唑-3-基）-N2-[3-（4-吗啉基）丙基]-2,4-嘧啶二胺；RACGTPASE抑制剂（EHOP-016）；Ehop-016抑制剂；EHOP-016游离态；N4-(9-乙基-9H-咔唑-3-基)-N2-[3-(4-吗啉基)丙基]-2,4-嘧啶二胺；EHOP-016
• 英文名称: EHop-016
• 英文别名: N4-(9-Ethyl-9H-carbazol-3-yl)-N2-(3-morpholinopropyl)pyrimidine-2,4-diamine；4-N-(9-ethylcarbazol-3-yl)-2-N-(3-morpholin-4-ylpropyl)pyrimidine-2,4-diamine
• CAS: 1380432-32-5
• 化学式: C₂₅H₃₀N₆O
• 分子量: 430.553
• InChiKey: AFTZZRFCMOAFCR-UHFFFAOYSA-N

物化性质

• 沸点：
  633.9±65.0 °C(Predicted)
• 密度：
  1.27
• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  67.2
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• WGK Germany：
  3
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : EHOP-016
CAS-No. : 1380432-32-5
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008.
This substance is not classified as dangerous according to Directive 67/548/EEC.
Label elements
This substance is not classified as dangerous according to Directive 67/548/EEC.
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : N4-(9-Ethyl-9H-carbazol-3-yl)-N2-[3-(4-morpholinyl)propyl]-2,4-
pyrimidinediamine
Formula : C25H30N6O
Molecular Weight : 430,55 g/mol

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Section 4. FIRST AID MEASURES
Description of first aid measures
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration.
In case of skin contact
Wash off with soap and plenty of water.
In case of eye contact
Flush eyes with water as a precaution.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water.
Most important symptoms and effects, both acute and delayed
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Indication of any immediate medical attention and special treatment needed
no data available

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Section 5. FIREFIGHTING MEASURES
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx)
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

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Section 6. ACCIDENTAL RELEASE MEASURES
Personal precautions, protective equipment and emergency procedures
Avoid dust formation. Avoid breathing vapors, mist or gas.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
Sweep up and shovel. Keep in suitable, closed containers for disposal.
Reference to other sections
For disposal see section 13.

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Section 7. HANDLING AND STORAGE
Precautions for safe handling
Provide appropriate exhaust ventilation at places where dust is formed.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Recommended storage temperature: 2 - 8 °C
Specific end uses
no data available

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Section 8. EXPOSURE CONTROLS/PERSONAL PROTECTION
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
General industrial hygiene practice.
Personal protective equipment
Eye/face protection
Use equipment for eye protection tested and approved under appropriate government standards
such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
Choose body protection in relation to its type, to the concentration and amount of dangerous
substances, and to the specific work-place., The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Respiratory protection is not required. Where protection from nuisance levels of dusts are desired,
use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and
approved under appropriate government standards such as NIOSH (US) or CEN (EU).

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Section 9. PHYSICAL AND CHEMICAL PROPERTIES
Information on basic physical and chemical properties
a) Appearance Form: solid
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing no data available
point
f) Initial boiling point and no data available
boiling range
g) Flash point not applicable
h) Evaporation rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density no data available
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Autoignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

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Section 10. STABILITY AND REACTIVITY
Reactivity
no data available
Chemical stability
no data available
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available

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Section 11. TOXICOLOGICAL INFORMATION
Information on toxicological effects
Acute toxicity
no data available
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Potential health effects
Inhalation May be harmful if inhaled. May cause respiratory tract irritation.
Ingestion May be harmful if swallowed.
Skin May be harmful if absorbed through skin. May cause skin irritation.
Eyes May cause eye irritation.
Signs and Symptoms of Exposure
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Additional Information
RTECS: Not available

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Section 12. ECOLOGICAL INFORMATION
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
no data available
Other adverse effects
no data available

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Section 13. DISPOSAL CONSIDERATIONS
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company.
Contaminated packaging
Dispose of as unused product.

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Section 14. TRANSPORT INFORMATION
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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SECTION 15 - REGULATORY INFORMATION
N/A

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

生物活性

EHop-016 是一种有效的选择性 Rac GTPase Rac1 和 Rac3 抑制剂。在 MDA-MB-435 细胞中，它抑制了 Rac1 的活性，IC50 为 1.1 μM。EHop-016 还能抑制 Vav2 与 Rac 激活的 PAK1 相互作用、片状脂蛋白形成和细胞迁移。

体外研究

在 MDA-MB-435 细胞中，使用 EHop-016（浓度为 1-10 μM；处理时间 24 小时）可抑制 Rac1 和 Rac3 活性。更高浓度的 EHop-016 还能抑制同源 Cdc42 的活性。在 Vav2 高活跃水平的 MDA-MB-435 细胞中，EHop-016 抑制了 Vav2 与无核苷酸 Rac1(G15A) 的结合。

此外，在 MDA-MB-231 迁移性乳腺癌细胞中，EHop-016 抑制了 Rac 活性并减少了这两种细胞线中的 lamellipodia 形成。它还通过降低 PAK1（p21-激活激酶 1）活性和迁移性癌细胞的定向迁移来减少 Rac 的下游效应。

EHop-016 还通过下调 Akt 和 Jun 激酶活性、c-Myc 和 Cyclin D 表达以及增加 caspase 3/7 活性而影响癌细胞存活率。

Western Blot 分析

• 细胞系： MDA-MB-435 细胞
• 浓度： 1 μM, 2 μM, 4 μM, 5 μM, 10 μM
• 孵育时间： 24 小时
• 结果： Rac3 活性被抑制了 58%。

体内研究

在雌性裸鼠（4-5 周龄）中，通过腹腔注射 EHop-016（剂量为 10 mg/kg 和 25 mg/kg；每周三次；共 55 天），显著减少了乳腺脂肪垫肿瘤的生长、转移和血管生成。

动物模型

• 动物种类： 去胸腺裸鼠（4-5 周龄）
• 药物剂量： 10 mg/kg, 25 mg/kg
• 给药方式： 腹腔注射；每周三次；共 55 天
• 结果： 显著减少了乳腺脂肪垫肿瘤的生长、转移和血管生成。

反应信息

• 作为产物：
  描述：

  3-氨基-9-乙基咔唑 在 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 异丙醇 为溶剂， 反应 10.0h， 生成 RACGTPASE抑制剂(EHOP-016)
  参考文献：
  名称：

  NOVEL CARBAZOLE EHOP-016 DERIVATIVES AS ANTI-CANCER AND ANTI-MIGRATORY AGENTS

  摘要：

  本文介绍了一系列EHop-016衍生物，通过设计和合成模拟其更有利的“U”形构象的化合物，这对于抑制Rac的活性至关重要。基于对EHop-016的建模研究，具有更严格结构构象的化合物可以模拟这种“U”形构象，从而提高对转移性细胞的抗迁移活性。披露了抑制对抗过度增殖和肿瘤性疾病有用的RhoGTP酶的化合物。具体来说，这些化合物抑制了在癌症和转移中信号通路中过度活跃或过度表达的Rac和Cdc42 GTP酶。还披露了治疗癌症和过度增殖性疾病的方法。

  公开号：

  US20190125746A1

文献信息

• Novel Small-Molecule Inhibitors of Rac1 in Metastatic Breast Cancer
  申请人：University of Puerto Rico

  公开号：US20130172552A1

  公开（公告）日：2013-07-04

  A novel inhibitor of Rac activity based on the structure of the established Rac/Rac-GEF inhibitor NSC23766 is discloses. The compound EHop-016, with an IC50 of 1.1 μM, is a 100-fold more efficient inhibitor of Rac activity than NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations ≦5 mM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells, EHop-016 (≦5 mM) inhibits the association of the Rac-GEF Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs. EHop-016 does not affect the association of the Rac-GEF Tiam-1 with Rac1(G15A) at similar concentrations. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac-downstream effects of p21-activated kinase (PAK)1 activity and directed migration of metastatic cancer cells. At low concentrations (<5 μM), EHop-016 does not affect cell viability.

  基于已建立的Rac/Rac-GEF抑制剂NSC23766的结构，揭示了一种新的Rac活性抑制剂。该化合物EHop-016的IC50为1.1μM，比NSC23766更有效地抑制Rac活性100倍。EHop-016在浓度≦5 mM时对Rac1和Rac3具有特异性。在较高浓度下，EHop-016会抑制密切同源物Cdc42。在MDA-MB-435细胞中，EHop-016（≦5 mM）抑制了Rac-GEF Vav2与核苷酸游离的Rac1(G15A)的结合，后者对激活的GEFs具有高亲和力。在相似浓度下，EHop-016不会影响Rac-GEF Tiam-1与Rac1(G15A)的结合。EHop-016还抑制了MDA-MB-231转移性乳腺癌细胞的Rac活性，并减少了两种细胞系中Rac定向的膜足形成。EHop-016降低了Rac下游效应p21激活的激酶（PAK）1活性和转移性癌细胞的定向迁移。在低浓度（<5μM）下，EHop-016不影响细胞存活。
• Carbazole EHop-016 derivatives as anti-cancer and anti-migratory agents
  申请人：UNIVERSITY OF PUERTO RICO

  公开号：US10729689B2

  公开（公告）日：2020-08-04

  A series of novel EHop-016 derivatives is presented herein via designing and synthesizing compounds that mimics its more favorable “U-shaped” conformation that appears to be critical for inhibitory activity against Rac. Based on modeling studies on EHop-016, compounds with a more rigid structural conformation can mimic this “U-shaped” conformation would improve the anti-migration activity against metastatic cells. Compounds are disclosed that inhibit RhoGTPases that are useful for inhibiting hyperprofilerative and neoplastic diseases, for instance compounds of formula (I) Specifically, the compounds inhibit the GTPases Rac and Cdc42 that are overactive or overexpressed in signaling pathways in cancer and metastasis. Methods for treatment of cancer and hyperproliferative diseases are disclosed.

  本文介绍了一系列新型 EHop-016 衍生物，通过设计和合成化合物来模拟其更有利的 "U 形 "构象，这种构象似乎是抑制 Rac 活性的关键。根据对 EHop-016 的建模研究，具有更坚硬结构构象的化合物可以模拟这种 "U 形 "构象，从而提高对转移细胞的抗迁移活性。已公开的抑制 RhoGTP 酶的化合物可用于抑制畸形和肿瘤性疾病，例如式 (I) 的化合物 具体而言，这些化合物可抑制在癌症和转移的信号通路中过度活跃或过度表达的 GTP 酶 Rac 和 Cdc42。本研究还公开了治疗癌症和过度增殖性疾病的方法。
• Method of treating VEGF/VEGFR resistant prostate cancer by combining the therapy with RAC1 inhibitors
  申请人：University of Massachusetts

  公开号：US10947537B2

  公开（公告）日：2021-03-16

  Methods and compositions for treating cancer, e.g., prostate cancer, using a combination of P-Rex1 or Rac1 inhibitors and VEGF/VEGFR-targeted therapy.

  利用P-Rex1或Rac1抑制剂和VEGF/VEGFR靶向疗法联合治疗癌症（如前列腺癌）的方法和组合物。
• Carbazole EHop-016 derivatives as anticancer and anti-migratory agents
  申请人：UNIVERSITY OF PUERTO RICO

  公开号：US11446299B2

  公开（公告）日：2022-09-20

  A series of novel EHop-016 derivatives is presented herein via designing and synthesizing compounds that mimics its more favorable “U-shaped” conformation that appears to be critical for inhibitory activity against Rac. Based on modeling studies on EHop-016, compounds with a more rigid structural conformation can mimic this “U-shaped” conformation and would improve the anti-migration activity against metastatic cells. Compounds are disclosed that inhibit RhoGTPases that are useful for inhibiting hyperprofilerative and neoplastic diseases, for instance compounds of formula Specifically, the compounds inhibit the GTPases Rac and Cdc42 that are overactive or overexpressed in signaling pathways in cancer and metastasis. Methods for treatment of cancer and hyperproliferative diseases are disclosed.

  本文介绍了一系列新型 EHop-016 衍生物，通过设计和合成化合物来模拟其更有利的 "U 形 "构象，这种构象似乎对 Rac 的抑制活性至关重要。根据对 EHop-016 的建模研究，具有更刚性结构构象的化合物可以模拟这种 "U 形 "构象，从而提高对转移细胞的抗迁移活性。已公开的抑制 RhoGTP 酶的化合物可用于抑制畸形和肿瘤性疾病，例如式 具体而言，这些化合物可抑制在癌症和转移的信号通路中过度活跃或过度表达的 GTP 酶 Rac 和 Cdc42。本研究还公开了治疗癌症和过度增殖性疾病的方法。
• Combination Therapy
  申请人：University of Massachusetts

  公开号：US20190040396A1

  公开（公告）日：2019-02-07

  Methods and compositions for treating cancer, e.g., prostate cancer, using a combination of P-Rex1 or Rac1 inhibitors and VEGF/VEGFR-targeted therapy.