エトポシド
概要
説明
作用機序
科学的研究の応用
エトポシドは、以下のものを含む、幅広い科学研究における応用範囲を持っています。
準備方法
エトポシドは、ポドフィロトキシンを出発物質として、半合成プロセスによって合成されます。 一般的な方法の1つは、4'-脱メチルエピポドフィロトキシンと2,3-ジ-O-ジクロロアセチル-(4,6-O-エチリデン)-β-D-グルコピラノースを、トリメチルシリルトリフルオロメタンスルホネート（TMSOTf）の存在下で直接縮合させて、4'-脱メチルエピポドフィロトキシン-4-(2,3-ジ-O-ジクロロアセチル-4,6-O-エチリデン)-β-D-グルコピラノシドを得て、これをエトポシドに変換する方法です . この方法は、既存の手法と比較して、収率が向上し、反応時間が短縮され、分離操作が容易になるという利点があります .
化学反応の分析
エトポシドは、以下のものを含む、いくつかのタイプの化学反応を起こします。
酸化: エトポシドは、酸化されてO-キノン誘導体となり、これがDNAに対する活性に重要な役割を果たします.
還元: 還元反応により、エトポシドはヒドロキノン型に変換されます。
置換: エトポシドは、特にグルコピラノシド部分で、置換反応を起こす可能性があります。
これらの反応で使用される一般的な試薬および条件には、過酸化水素などの酸化剤と、水素化ホウ素ナトリウムなどの還元剤が含まれます。 これらの反応から生成される主要な生成物には、エトポシドのO-キノン誘導体とヒドロキノン誘導体が含まれます .
類似化合物との比較
エトポシドは、テニポシドやポドフィロトキシンなど、他のポドフィロトキシン誘導体と類似しています。 エトポシドは、トポイソメラーゼIIの特異的な阻害と、幅広い癌治療への利用において独自性を持ちます .
特性
CAS番号 |
33419-42-0 |
|---|---|
分子式 |
C29H32O13 |
分子量 |
588.6 g/mol |
IUPAC名 |
(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7S,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one |
InChI |
InChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25+,26-,27-,29+/m1/s1 |
InChIキー |
VJJPUSNTGOMMGY-QBUITQBFSA-N |
不純物 |
The following impurities are limited by the requirements of The British Pharmacopoeia: 4'-carbenzoxy ethylidene lignan P, picroethylidene lignan P, alpha-ethylidene lignan P, lignan P and 4'-demethylepipodophyllotoxin. |
SMILES |
CC1OCC2C(O1)C(C(C(O2)OC3C4COC(=O)C4C(C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O |
異性体SMILES |
C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@@H]([C@@H](O2)O[C@H]3[C@H]4COC(=O)[C@@H]4[C@@H](C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O |
正規SMILES |
CC1OCC2C(O1)C(C(C(O2)OC3C4COC(=O)C4C(C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O |
外観 |
White to off-white solid powder |
Color/Form |
Crystals from methanol |
melting_point |
236-251 °C |
| 33419-42-0 | |
物理的記述 |
Solid |
ピクトグラム |
Irritant; Health Hazard |
純度 |
>98% (or refer to the Certificate of Analysis) |
賞味期限 |
>2 years if stored properly |
溶解性 |
Very soluble in methanol, chloroform; slightly soluble in ethanol, sparingly soluble in water. Sol in alc: approx 0.76 mg/ml Water solubility: approx 0.08 mg/mL |
保存方法 |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
同義語 |
alpha-D-Glucopyranosyl Isomer Etoposide Celltop Demethyl Epipodophyllotoxin Ethylidine Glucoside Eposide Eposin Eto GRY Eto-GRY Etomedac Etopos Etoposide Etoposide Pierre Fabre Etoposide Teva Etoposide, (5a alpha)-Isomer Etoposide, (5a alpha,9 alpha)-Isomer Etoposide, (5S)-Isomer Etoposide, alpha D Glucopyranosyl Isomer Etoposide, alpha-D-Glucopyranosyl Isomer Etoposido Ferrer Farma Exitop Lastet NSC 141540 NSC-141540 NSC141540 Onkoposid Riboposid Teva, Etoposide Toposar Vépéside Sandoz Vépéside-Sandoz Vepesid VP 16 VP 16 213 VP 16-213 VP 16213 VP-16 VP16 |
蒸気圧 |
5.4X10-23 mm Hg at 25 °C /Estimated/ |
製品の起源 |
United States |
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| 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
Q1: What is the primary molecular target of Etoposide?
A1: Etoposide primarily targets DNA Topoisomerase II (Topo II), an enzyme essential for DNA replication and repair. [, ] It inhibits Topo II by trapping the enzyme in a complex with cleaved DNA, ultimately leading to DNA damage and cell death. []
Q2: How does Etoposide-induced DNA damage lead to cell death?
A2: Etoposide-induced DNA damage triggers a series of downstream events, including activation of p53, a tumor suppressor protein. [] p53 can initiate cell cycle arrest, giving the cell time to repair the damage, or, if the damage is too extensive, it can trigger apoptosis (programmed cell death). [, ]
Q3: What is the molecular formula and weight of Etoposide?
A3: While this specific information is not provided in the research excerpts, Etoposide's molecular formula is C29H32O13 and it has a molecular weight of 588.56 g/mol. This information can be readily found in publicly available chemical databases.
Q4: How does Etoposide perform in liposomal formulations for pulmonary delivery?
A5: Research indicates that Etoposide can be successfully incorporated into liposomes for pulmonary delivery. Freeze-dried liposomal formulations of Etoposide, using trehalose as a cryoprotectant, demonstrated good stability in terms of particle size and drug content for up to six months when stored at both ambient and refrigerated temperatures. []
Q5: What is the role of P-glycoprotein (P-gp) in the pharmacokinetics of Etoposide?
A6: P-glycoprotein (P-gp), encoded by the ABCB1 gene, plays a significant role in the absorption, distribution, and excretion of Etoposide. [, ] It acts as a transport protein, limiting the oral uptake of Etoposide and mediating its excretion across the gut wall. []
Q6: How does the ABCB1 (C1236T) polymorphism affect Etoposide's pharmacokinetics?
A7: The ABCB1 (C1236T) polymorphism has been shown to affect the transport activity of P-glycoprotein. Research using recombinant Caco-2 cell lines, expressing either the wild-type or variant P-gp, revealed that the variant P-gp transports Etoposide to a greater extent compared to the wild-type protein. [] This suggests that individuals with the ABCB1 (C1236T) polymorphism might experience altered Etoposide pharmacokinetics and potentially different therapeutic outcomes.
Q7: What is the bioavailability of oral Etoposide?
A8: The oral bioavailability of Etoposide is highly variable, ranging from 25% to 80% among cancer patients. [] This variability can be attributed, in part, to variations in transporter expression or activity, such as P-glycoprotein (P-gp), which influences the absorption and efflux of Etoposide. [, ]
Q8: What is the relationship between Etoposide exposure and neutropenia?
A9: Studies indicate a strong correlation between exposure to the free, pharmacologically active form of Etoposide and the risk of neutropenia, a significant decrease in neutrophils, a type of white blood cell. [] The higher the exposure to free Etoposide, the greater the risk of developing neutropenia.
Q9: What is the efficacy of oral Etoposide in treating metastatic breast cancer?
A10: A pooled analysis of twelve studies investigating the use of oral Etoposide in metastatic breast cancer revealed a moderate clinical effectiveness, with a pooled response rate of 18.5% and a clinical benefit rate of 45.8%. []
Q10: What are the known mechanisms of resistance to Etoposide?
A11: Resistance to Etoposide can arise through various mechanisms, including decreased expression of Topoisomerase II (Topo II), the primary target of Etoposide. [] Other mechanisms involve the multidrug-resistant phenotypes encoded by the mdr1 and MRP (multidrug resistance-associated protein) genes. []
Q11: What are the potential long-term effects of Etoposide treatment?
A13: Etoposide treatment has been associated with an increased risk of developing secondary acute myeloid leukemia (s-AML), a serious blood cancer. [] This risk appears to be higher when Etoposide is used in combination with cyclophosphamide. The latency period for developing s-AML after Etoposide treatment is typically 1-3 years, though longer periods have been reported. []
Q12: Have nanosuspensions been explored as a potential drug delivery system for Etoposide?
A14: Yes, research has investigated the use of Etoposide-loaded bovine serum albumin (BSA) nanosuspensions for parenteral delivery. [] This approach aims to improve the delivery of Etoposide, a poorly water-soluble drug, and potentially enhance its therapeutic efficacy while minimizing side effects.
Q13: What analytical techniques are commonly used to quantify Etoposide in biological samples?
A15: High-performance liquid chromatography (HPLC) is frequently employed to quantify Etoposide in biological samples, such as plasma. [, , ] Fluorescence detection is often used in conjunction with HPLC to enhance sensitivity. []
Q14: How do transporters like ABCC2 and ABCC3 influence Etoposide pharmacokinetics?
A16: ABCC2, also known as MRP2, plays a crucial role in the hepatobiliary excretion of Etoposide. [] ABCC3 (MRP3) contributes to the elimination of Etoposide glucuronide, a metabolite of Etoposide, from the liver into the bloodstream, which is subsequently eliminated in urine. []
試験管内研究製品の免責事項と情報
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