5-甲基-4-硝基-3-异噁唑羧酸 | 960225-75-6

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 中文名称: 5-甲基-4-硝基-3-异噁唑羧酸
• 中文别名: 5-甲基-4-硝基-3-异恶唑羧酸
• 英文名称: 5-methyl-4-nitroisoxazole-3-carboxylic acid
• 英文别名: 5-methyl-4-nitro-1,2-oxazole-3-carboxylic acid；5-Methyl-4-nitro-3-isoxazolecarboxylic acid
• CAS: 960225-75-6
• 化学式: C₅H₄N₂O₅
• mdl: MFCD11520861
• 分子量: 172.097
• InChiKey: GIRMISJOXYRPLD-UHFFFAOYSA-N

物化性质

• 沸点：
  394.9±42.0 °C(Predicted)
• 密度：
  1.622±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 海关编码：
  2934999090
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: 5-Methyl-4-nitro-3-isoxazolecarboxylic acid
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: 5-Methyl-4-nitro-3-isoxazolecarboxylic acid
CAS number: 960225-75-6

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C5H4N2O5
Molecular weight: 172.1

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

反应信息

• 作为反应物：
  描述：

  5-甲基-4-硝基-3-异噁唑羧酸 在 sodium dithionite 、 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 5.0h， 生成 N-(3-(4-benzhydrylpiperazine-1-carbonyl)-5-methylisoxazol-4-yl)acetamide
  参考文献：
  名称：

  Development of small-molecule probes that selectively kill cells induced to express mutant RAS

  摘要：

  Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.047
• 作为产物：
  描述：

  5-甲基异恶唑-3-甲酸 在 sodium nitrate 、 硫酸 作用下， 以97 %的产率得到5-甲基-4-硝基-3-异噁唑羧酸
  参考文献：
  名称：

  具有取代异恶唑片段的新鬼臼毒素和鬼臼毒素衍生物

  摘要：

  合成了一系列鬼臼毒素和鬼臼毒素酯，甲基异恶唑片段在杂环的 4 位含有一个卤素原子或一个硝基。通过溴化、碘化或硝化 5-甲基异恶唑-3-羧酸获得起始异恶唑羧酸，然后通过在 DCC/DMAP 或 EDC/DMAP 系统中进行酯化将其转化为目标酯。鬼臼毒素和鬼臼毒素酯与含碘异恶唑衍生物的分子对接结果预测了它们分别与微管蛋白和拓扑异构酶II结合的能力，不排除与目标蛋白形成卤素键的可能性。初步生物筛选表明，所有化合物均以 100 nmol L −1的浓度获得处理 72 小时后导致 A549 和 VA13 细胞数量减少 40-60%。

  DOI：

  10.1007/s11172-023-3868-5

文献信息

• Structure–activity relationships of GPX4 inhibitor warheads
  作者：John K. Eaton、Laura Furst、Luke L. Cai、Vasanthi S. Viswanathan、Stuart L. Schreiber

  DOI：10.1016/j.bmcl.2020.127538

  日期：2020.12

  masked nitrile oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here, we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. We find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to inhibit GPX4 despite the expected

  GPX4 的直接抑制需要活性位点硒代半胱氨酸的共价修饰。虽然表型筛选表明活化的烷基氯化物和掩蔽的腈氧化物可以共价抑制 GPX4，但缺乏对具有抑制细胞 GPX4 能力的潜在亲电弹头的系统评估。在这里，我们在几个不同的 GPX4 靶向支架上调查了超过 25 个亲电子弹头。我们发现，尽管硒代半胱氨酸残基具有预期的亲核性，但与氯乙酰胺相比，反应性减弱的亲电试剂无法抑制 GPX4。然而，我们在本研究中发现的高反应性丙炔酰胺可以替代 GPX4 抑制剂中的氯乙酰胺和硝基异恶唑弹头。我们的观察表明，亲电掩蔽策略，
• Kinetics of hydrolysis of five-membered C-nitroheterocycles: pyrazole, imidazole, 1,2,4-triazole, and isoxazole derivatives
  作者：L. A. Trukhacheva、V. I. Levina、N. B. Grigor’ev、A. P. Arzamastsev、I. L. Dalinger、I. A. Vatsadze、G. P. Popova、S. A. Shevelev、V. G. Granik

  DOI：10.1007/s11172-006-0195-1

  日期：2005.12

  dinitro derivatives of five-membered heterocycles, viz., pyrazole, imidazole, 1,2,4-triazole, and isoxazole, is accompanied by the elimination of the nitro group in the form of a nitrite anion. The hydrolysis kinetics was studied by the polarographic and photometric methods. The experimentally determined hydrolysis rate constants depend on the nature of the heterocycle. A possible mechanism for hydrolytic

  五元杂环的单和二硝基衍生物（即吡唑、咪唑、1,2,4-三唑和异恶唑）的碱性水解伴随着硝基以亚硝酸根阴离子的形式被消除。通过极谱法和光度法研究了水解动力学。实验确定的水解速率常数取决于杂环的性质。根据计算出的反应热力学参数（ΔG≠、ΔH≠、ΔS≠），提出了所研究化合物水解转化的可能机制。
• [EN] GPX4 PROTEIN DEGRADATION-INDUCING COMPOUND<br/>[FR] COMPOSÉ INDUISANT LA DÉGRADATION DE LA PROTÉINE GPX4<br/>[KO] GPX4 단백질 분해 유도 화합물
  申请人：UPPTHERA

  公开号：WO2022119362A1

  公开（公告）日：2022-06-09

  본 발명은 GPX4 단백질 분해 유도 화합물에 관한 것이다. 구체적으로, 본 발명은 GPX4 단백질 결합 모이어티와 CRBN E3 유비퀴틴 라이게이즈 결합 모이어티가 화학적 링커로 연결된 이기능성 화합물, 이의 제조방법, 이를 활용한 GPX4 단백질의 분해 방법 및 GPX4 관련 질환 또는 페롭토시스 관련 질환의 예방 또는 치료 용도 등을 제공한다.

  这项发明涉及GPX4蛋白质降解诱导化合物。具体而言，本发明提供了一种将GPX4蛋白质结合模因子和CRBN E3泛素连接酶结合模因子通过化学连接剂连接的这种功能化合物、其制备方法、利用其分解GPX4蛋白质的方法以及预防或治疗与GPX4相关疾病或过氧化脂质症相关疾病的用途等。
• Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells
  作者：Han Wang、Chao Wang、Bingru Li、Cangxin Zheng、Guoquan Liu、Zhenming Liu、Liangren Zhang、Ping Xu

  DOI：10.1016/j.ejmech.2023.115343

  日期：2023.6

  growth inhibition effect with the IC50 value of 0.1 μM in HT1080 cells. Mechanism research showed that DC-2 induced GPX4 degradation via the ubiquitin-proteasome pathway and autophagy-lysosome pathway. GPX4 degradation induced by DC-2 could result in the accumulation of ROS and subsequent ferroptosis. The pharmacodynamics study showed that DC-2 could reduce the GPX4 level in HT1080 tumor tissue in mice

  Ferroptosis 是一种由脂质过氧化积累引起的铁依赖性细胞死亡。谷胱甘肽过氧化物酶 4 (GPX4) 是一种抗氧化酶，也是铁死亡的主要调节因子。靶向 GPX4 已成为一种很有前途的癌症治疗策略。在本文中，我们设计并合成了一系列使用 ML210 作为弹头的 GPX4 降级器。其中DC-2被发现在HT1080细胞中具有最好的降解活性，DC 50值为0.03 μM。对HT1080细胞也有明显的细胞生长抑制作用，IC 50值为0.1 μM。机制研究表明， DC-2通过泛素-蛋白酶体途径和自噬-溶酶体途径诱导 GPX4 降解。DC-2诱导的 GPX4 降解可能导致 ROS 的积累和随后的铁死亡。药效学研究表明，DC-2可降低小鼠HT1080肿瘤组织中的GPX4水平，具有良好的安全性。最重要的是，已发现一种有效且安全的化合物DC-2可诱导 GPX4 降解和随后的铁死亡。该研究可能为开发具有新机制的高效、安全的癌症治疗药物奠定基础。
• 一种GPX4蛋白降解剂及其制备方法和应用、一种抗肿瘤细胞药物
  申请人：北京大学

  公开号：CN115724836A

  公开（公告）日：2023-03-03

  本发明提供了一种GPX4蛋白降解剂及其制备方法和应用、一种抗肿瘤细胞药物，属于药物应用技术领域。本发明提供的降解剂具有蛋白降解靶向嵌合体(PROTACs)分子结构，以ML210单元为靶向单元，能够有效结合靶蛋白。A2取代基作为结合E3泛素连接酶复合物的小分子配体，A1取代基作为将两个配体连接起来连接基。因为PROTAC与靶蛋白和E3连接酶需要在空间上形成构象稳定的三元复合物才能发挥降解活性，故PROTAC策略具有可增强药物分子靶点选择性的优势，因此GPX4蛋白降解剂能够特异性识并靶向GPX4蛋白，并将GPX4蛋白有效泛素化，从而诱导肿瘤细胞铁死亡。