奥沙利铂
描述
奥沙利铂是一种铂类化疗药物，主要用于治疗结直肠癌。它属于含铂抗肿瘤药物类，因其具有与 DNA 形成交联的能力而闻名，从而抑制 DNA 复制和转录。这种化合物已证明在治疗各种癌症类型方面有效，包括结直肠癌、卵巢癌和胰腺癌 .
科学研究应用
奥沙利铂在科学研究中具有广泛的应用，特别是在化学、生物学、医学和工业领域。
化学： 在化学领域，奥沙利铂被用作模型化合物，用于研究铂类药物与 DNA 和其他生物分子的相互作用。研究人员调查其反应性和结合特性，以开发新的更有效的铂类药物 .
生物学： 在生物学研究中，奥沙利铂用于研究癌细胞耐药机制。科学家探索癌细胞如何对铂类药物产生耐药性，并寻找克服这种耐药性的方法 .
医学： 在医学领域，奥沙利铂是治疗结直肠癌的基石。它通常与其他化疗药物（如氟尿嘧啶和亚叶酸钙）一起使用，组成 FOLFOX 等方案。临床试验继续探索其治疗其他类型癌症的疗效 .
工业： 在制药行业，奥沙利铂被生产并配制成可注射溶液，用于临床使用。其生产涉及严格的质量控制措施，以确保其对患者的安全性和有效性 .
作用机制
奥沙利铂通过与 DNA 形成共价键发挥作用，导致 DNA 交联的形成。这些交联阻止 DNA 复制和转录，最终导致细胞死亡。奥沙利铂的主要分子靶点是 DNA 中的嘌呤碱基，在那里它形成链内和链间交联 .
参与奥沙利铂作用机制的途径包括激活 DNA 损伤应答途径，导致细胞周期停滞和凋亡。该化合物还干扰癌细胞的修复机制，使其更容易受到其细胞毒作用的影响 .
生化分析
Biochemical Properties
Oxaliplatin interacts with various enzymes, proteins, and other biomolecules. Its mechanism of action primarily involves DNA damage through DNA crosslinking, particularly intrastrand and interstrand crosslinking . The structure of oxaliplatin allows its adducts to bind mismatch repair proteins to DNA more difficultly compared to cisplatin or carboplatin’s adducts, resulting in greater cytotoxic effects .
Cellular Effects
Oxaliplatin has a cytotoxic effect in a broad range of cell lines, including colon, ovarian, and lung cancer . It damages the DNA of cells and stops it from being copied. This stops or slows the growth of cancer cells and other rapidly growing cells and causes them to die .
Molecular Mechanism
The molecular mechanism of Oxaliplatin involves the formation of platinum-DNA adducts. The retention of the bulky DACH ring by activated oxaliplatin results in the formation of these adducts, which appear to be more effective at blocking DNA replication and are more cytotoxic than adducts formed from cisplatin .
Temporal Effects in Laboratory Settings
The pharmacokinetics of unbound platinum in plasma ultrafiltrate after oxaliplatin administration is triphasic, characterized by a short initial distribution phase and a long terminal elimination phase . No accumulation was observed in plasma ultrafiltrate after 130 mg/m^2 every 3 weeks or 85 mg/m^2 every 2 weeks .
Dosage Effects in Animal Models
In animal models, the effects of Oxaliplatin vary with different dosages. For example, in mice, PKM2 silencing induced resistance in HT29 and SW480 cells and sensitivity in HCT116 cells . The highest recommended dose of oxaliplatin in patients is 110 mg/m^2 (2.97 mg/kg) .
Metabolic Pathways
Oxaliplatin is involved in various metabolic pathways. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy-related metabolic pathways including fatty acid oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway .
Transport and Distribution
Oxaliplatin is transported and distributed within cells and tissues. The copper transporter 1 seems to be of particular importance for cisplatin uptake in tumor cells, while the organic cation transporter (OCT) 2, due to its specific organ distribution, may play a major role in the development of undesired cisplatin side effects .
Subcellular Localization
Oxaliplatin undergoes nuclear translocation in response to oxaliplatin in HCT116 and HT29 cells but not in OXA-resistant HTOXAR3 cells . This suggests that the subcellular localization of Oxaliplatin may play a role in its effectiveness and resistance.
准备方法
合成路线和反应条件： 奥沙利铂是通过多步合成过程合成的，该过程涉及铂化合物与特定配体的反应。主要的合成路线涉及顺式-二碘(反式-1,2-二氨基环己烷)铂(II)与草酸的反应。反应条件通常包括控制温度和 pH 值，以确保形成所需的产物 .
工业生产方法： 在工业环境中，奥沙利铂是在大型反应器中生产的，反应条件经过精心控制，以实现高产量和高纯度。该过程涉及使用高纯度起始材料和溶剂，最终产品经过严格的质量控制措施，以确保其有效性和安全性 .
化学反应分析
反应类型： 奥沙利铂会经历几种类型的化学反应，包括取代、氧化和还原。最显著的反应是它与 DNA 形成共价键的能力，导致形成链内和链间交联 .
常用试剂和条件： 涉及奥沙利铂的反应通常需要特定试剂，例如氯离子、水和各种有机溶剂。条件通常包括控制温度和 pH 值，以促进所需的化学转化 .
主要形成的产物： 奥沙利铂反应形成的主要产物是 DNA 加合物，它们是其细胞毒作用的原因。这些加合物阻止 DNA 复制和转录，导致细胞死亡 .
相似化合物的比较
奥沙利铂经常与其他铂类化疗药物（如顺铂和卡铂）进行比较。虽然这三种化合物都具有相似的作用机制，但奥沙利铂具有独特的特性，使其与其他化合物有所区别。
类似化合物：
奥沙利铂的独特性： 奥沙利铂的独特性在于它能够形成更稳定的 DNA 加合物，导致癌细胞的细胞毒性更强。它还具有不同的副作用特征，肾毒性和耳毒性发生率较低，但周围神经病变发生率较高 .
总之，奥沙利铂是一种重要的化疗药物，在科学研究和临床实践中具有广泛的应用。其独特的特性和作用机制使其成为抗癌斗争中宝贵的工具。
属性
| Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. | |
CAS 编号 |
61825-94-3 |
分子式 |
C8H14N2O4Pt |
分子量 |
397.29 g/mol |
IUPAC 名称 |
[(1R,2R)-2-azanidylcyclohexyl]azanide;oxalic acid;platinum(2+) |
InChI |
InChI=1S/C6H12N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-8H,1-4H2;(H,3,4)(H,5,6);/q-2;;+2/t5-,6-;;/m1../s1 |
InChI 键 |
DRMCATBEKSVAPL-BNTLRKBRSA-N |
SMILES |
C1CCC(C(C1)[NH-])[NH-].C(=O)(C(=O)[O-])[O-].[Pt+4] |
手性 SMILES |
C1CC[C@H]([C@@H](C1)[NH-])[NH-].C(=O)(C(=O)O)O.[Pt+2] |
规范 SMILES |
C1CCC(C(C1)[NH-])[NH-].C(=O)(C(=O)O)O.[Pt+2] |
外观 |
white solid powder |
沸点 |
100ºC |
| 63121-00-6 61825-94-3 |
|
物理描述 |
Solid |
Pictograms |
Irritant; Health Hazard |
纯度 |
>98% (or refer to the Certificate of Analysis) |
相关CAS编号 |
63121-00-6 63121-00-6 (SP-4-2 (trans)) |
保质期 |
>10 years if stored properly |
溶解度 |
Soluble in water at 4 mg/mL and DMSO at 20 mg/mL; slightly soluble in methanol; insoluble in ethanol. |
储存 |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
同义词 |
1,2 Diaminocyclohexane Platinum Oxalate 1,2-diaminocyclohexane platinum oxalate 1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II) ACT 078 ACT-078 ACT078 cis-oxalato-(trans-l)-1,2-diaminocyclohexane-platinum(II) Eloxatin Eloxatine L-OHP cpd oxalato-(1,2-cyclohexanediamine)platinum II oxaliplatin oxaliplatin, (SP-4-2-(1R-trans))-isomer oxaliplatin, (SP-4-2-(1S-trans))-isomer oxaliplatin, (SP-4-3-(cis))-isomer oxaliplatine Platinum(2+) ethanedioate (1R,2R)-1,2-cyclohexanediamine (1:1:1) platinum(II)-1,2-cyclohexanediamine oxalate |
产品来源 |
United States |
Retrosynthesis Analysis
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Strategy Settings
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| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
体外研究产品的免责声明和信息
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