ellipticine-N²-oxide

• 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: ellipticine-N²-oxide
• 英文别名: ellipticine-N2-oxide；ellipticine N-oxide
• 化学式: C₁₇H₁₄N₂O
• 分子量: 262.311
• InChiKey: JLMKYEURVHJLGD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.72
• 重原子数：
  20.0
• 可旋转键数：
  0.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  42.73
• 氢给体数：
  1.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  ellipticine-N²-oxide 在 对甲苯磺酰氯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以43%的产率得到3-chloro-ellipticine
  参考文献：
  名称：

  Ring D modifications of ellipticine. Part 2. Chlorination of ellipticine via its N-oxide and synthesis and selective acetylation of 5,6,11-trimethyl-5H-benzo[b]carbazole.

  摘要：

  The N-oxide of ellipticine can be used for the introduction of a chlorine atom at carbon-3 of the ellipticine nucleus. According to modelstudies with 5,8-dimethylisoquinoline-N-oxide the reaction is guided both by steric hindrance and by nitrogen-6 of the ellipticine system. Attempted nucleophilic substitution reactions of 3-chloro-ellipticines failed. The high cytostatic activity observed for 9-acetylellipticine stimulated us to prepare the corresponding deaza analogue. This compound was synthesized in 2 steps starting from 1-methylindole. Regioselective acetylation at C-2 was accomplished using acetic anhydride and ZnCl2 as a catalyst. Under a variety of other conditions the 2,9-diacetylproduct was formed and no 9-monoacetylated compound could be isolated. Just as the parent compound, the acetylated deazaellipticines showed only very low cytostatic activity.

  DOI：

  10.1016/s0040-4020(01)85018-3
• 作为产物：
  描述：

  椭圆玫瑰树碱 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 以90%的产率得到ellipticine-N²-oxide
  参考文献：
  名称：

  Ring D modifications of ellipticine. Part 2. Chlorination of ellipticine via its N-oxide and synthesis and selective acetylation of 5,6,11-trimethyl-5H-benzo[b]carbazole.

  摘要：

  The N-oxide of ellipticine can be used for the introduction of a chlorine atom at carbon-3 of the ellipticine nucleus. According to modelstudies with 5,8-dimethylisoquinoline-N-oxide the reaction is guided both by steric hindrance and by nitrogen-6 of the ellipticine system. Attempted nucleophilic substitution reactions of 3-chloro-ellipticines failed. The high cytostatic activity observed for 9-acetylellipticine stimulated us to prepare the corresponding deaza analogue. This compound was synthesized in 2 steps starting from 1-methylindole. Regioselective acetylation at C-2 was accomplished using acetic anhydride and ZnCl2 as a catalyst. Under a variety of other conditions the 2,9-diacetylproduct was formed and no 9-monoacetylated compound could be isolated. Just as the parent compound, the acetylated deazaellipticines showed only very low cytostatic activity.

  DOI：

  10.1016/s0040-4020(01)85018-3

文献信息

• Cytochrome <i>b</i>₅ Increases Cytochrome P450 3A4-Mediated Activation of Anticancer Drug Ellipticine to 13-Hydroxyellipticine Whose Covalent Binding to DNA Is Elevated by Sulfotransferases and <i>N</i>,<i>O</i>-Acetyltransferases
  作者：Marie Stiborová、Radek Indra、Michaela Moserová、Věra Černá、Martina Rupertová、Václav Martínek、Tomáš Eckschlager、René Kizek、Eva Frei

  DOI：10.1021/tx3000335

  日期：2012.5.21

  The antineoplastic alkaloid ellipticine is a prodrug, whose pharmacological efficiency is dependent on its cytochrome P450 (P450)- and/or peroxidase-mediated activation in target tissues. The P450 3A4 enzyme oxidizes ellipticine to five 3 metabolites, mainly to 13-hydroxy- and 12-hydroxyellipticine, the metabolites responsible for the formation of ellipticine-13-ylium and ellipticine-12-ylium ions that generate covalent DNA adducts. Cytochrome b(5) alters the ratio of ellipticine p metabolites formed by P450 3A4. While the amounts of the detoxication metabolites (7-hydroxy- and 9-hydroxyellipticine) were not changed with added cytochrome b(5), 12-hydroxy- and 13-hydroxyellipticine, and ellipticine N-2-oxide increased considerably. The P450 3A4-mediated oxidation of ellipticine was significantly changed only by holo-cytochrome 65, while apo-cytochrome b(5) without heme or Mn-cytochrome b(5) had no such effect. The change in amounts of metabolites resulted in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. The amounts of 13-hydroxy- and 12-hydroxyellipticine formed by P450 3A4 were similar, but more than 7-fold higher levels of the adduct. were formed by 13-hydrox-yellipticine than by 12-hydroxyellipticine. The higher susceptibility of 13-hydroxyellipticine toward heterolytic dissociation to ellipticine-13-ylium in comparison to dissociation of 12-hydroxyellipticine to ellipticine-12ylium, determined by quantum chemical calculations, explains this phenomenon. The amounts of the 13-hydroxyellipticinederived DNA adduct significantly increased upon reaction of 13-hydroxyellipticine with either 3'-phosphoadenosine-5'phosphosulfate or acetyl-CoA catalyzed by human sulfotransferases 1A1, 1A2, 1A3, and 2A1, or N,O-acetyltransferases 1 and 2. The calculated reaction free energies of heterolysis of the sulfate and acetate esters are by 10-17 kcal/mol more favorable than the energy of hydrolysis of 13-hydroxyellipticine, which could explain the experimental data.
• Ring D modifications of ellipticine. Part 2. Chlorination of ellipticine via its N-oxide and synthesis and selective acetylation of 5,6,11-trimethyl-5H-benzo[b]carbazole.
  作者：Adrian T. Boogaard、Upendra K. Pandit、Gerrit-Jan Koomen

  DOI：10.1016/s0040-4020(01)85018-3

  日期：1994.4

  The N-oxide of ellipticine can be used for the introduction of a chlorine atom at carbon-3 of the ellipticine nucleus. According to modelstudies with 5,8-dimethylisoquinoline-N-oxide the reaction is guided both by steric hindrance and by nitrogen-6 of the ellipticine system. Attempted nucleophilic substitution reactions of 3-chloro-ellipticines failed. The high cytostatic activity observed for 9-acetylellipticine stimulated us to prepare the corresponding deaza analogue. This compound was synthesized in 2 steps starting from 1-methylindole. Regioselective acetylation at C-2 was accomplished using acetic anhydride and ZnCl2 as a catalyst. Under a variety of other conditions the 2,9-diacetylproduct was formed and no 9-monoacetylated compound could be isolated. Just as the parent compound, the acetylated deazaellipticines showed only very low cytostatic activity.