1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione | 221216-02-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: 1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione
• 英文别名: 1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-one；NSC684664；P28UP6P9DZ；2-[[4-[2-(dimethylamino)ethylamino]-5,8-dihydroxy-9,10-dioxoanthracen-1-yl]amino]-N,N-dimethylethanamine oxide
• CAS: 221216-02-0
• 化学式: C₂₂H₂₈N₄O₅
• 分子量: 428.488
• InChiKey: DQFZXLFASNTVCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  120
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,4-Bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide 在 cytochrome P₄₅₀ reductase 、 extrahepatic P₄₅₀ enzyme CYP₂S₁ 、 甲酸铵 、 nicotinamide adenine dinucleotide phosphate 作用下， 以 乙腈 为溶剂， 生成 1,4-BIS[[2-(DIMETHYLAMINO)ETHYL]AMINO]-5,8-DIHYDROXYANTHRACENE-9,10-DIONE无结构图 、 1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione
  参考文献：
  名称：

  Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

  摘要：

  AQ4N [1,4-双{[2-(二甲氨基-N-氧化物)乙基]氨基}-5,8-二羟基蒽-9,10-二酮]，一种具有两个二甲氨基N-氧化物基团的前药，被转化为拓扑异构酶 II 抑制剂 AQ4 [1,4-双{[2-(二甲氨基)乙基]氨基}-5,8-二羟基-蒽-9,10-二酮]通过将 N-氧化物还原为二甲氨基取代基。早期研究表明，几种药物代谢细胞色素 P450 (P450) 酶可以在与实体瘤中类似的缺氧条件下催化这种还原反应。 CYP2S1和CYP2W1是从人类基因组中鉴定出的两种功能未知的肝外P450酶，它们在缺氧肿瘤细胞中的表达水平比正常组织中高得多。在这里，我们证明，与已发表的报告（Mol Pharmacol 76：1031-1043，2009）相反，CYP2S1 可以被 NADPH-P450 还原酶有效还原。最重要的是，与之前研究的所有 P450 酶相比，CYP2S1 和 CYP2W1 都是 AQ4N 还原活化为 AQ4 的更好催化剂。 CYP2S1和CYP2W1在肿瘤组织中的过度表达，以及它们对AQ4N激活的高催化活性，表明它们可用于抗癌前药的局部激活。

  DOI：

  10.1124/mol.110.065045

文献信息

• Reductive Heme-Dependent Activation of the <i>N</i>-Oxide Prodrug AQ4N by Nitric Oxide Synthase
  作者：Clinton R. Nishida、Paul R. Ortiz de Montellano

  DOI：10.1021/jm800496s

  日期：2008.8.1

  Anaerobic reduction of anticancer prodrugs is a promising route to achieve targeting and selectivity in anticancer drug design. Most reductive prodrug activations involve simple electron transfer from a flavoprotein and are not amenable to specific targeting. Here, we report that the N-oxide AQ4N is reduced by a nitric oxide synthase. This reduction involves interaction with the heme iron atom in the active site and is thus subject to specific protein constraints.
• Formulations of anthraquinone derivatives
  申请人：Halbert William Gavin

  公开号：US20070027136A1

  公开（公告）日：2007-02-01

  A stable, sterile aqueous solution of a compound of formula (I): in which A is a C alkylene group with a chain length between NH and N(O)R′R″ of at least 2 carbon atoms and R′ and R″ are each separately selected from C 1-4 alkyl groups and C 2-4 hydroxyalkyl and C 2-4 dihydroxyalkyl groups, or R′ and R″ together are a C 2-6 alkylene group, is formulated in a unit dosage form in a sealed container, said solution having a concentration of the compound of formula (I) up to 150 mg/ml and a pH in the range of 5 to 9. The solution may be prepared without a freeze drying step.
• Process for the preparation of aq4n
  申请人：Matthews Timothy William Ian

  公开号：US20070161808A1

  公开（公告）日：2007-07-12

  A process for the preparation of compound AQ4N of formula (2) or a salt or solvate thereof wherein the said process includes the reaction step: Formula (1), Formula (2), where compound AQ4 of formula (1) is oxidised to compound AQ4N of formula (2) with an oxidising agent at a reaction temperature not exceeding 10° C.
• US7276537B2
  申请人：——

  公开号：US7276537B2

  公开（公告）日：2007-10-02
• Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1
  作者：Clinton R. Nishida、Melody Lee、Paul R. Ortiz de Montellano

  DOI：10.1124/mol.110.065045

  日期：2010.9

  AQ4N [1,4-bis[2-(dimethylamino- N -oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N -oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N -oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report ( Mol Pharmacol 76: 1031–1043, 2009), is efficiently reduced by NADPH–P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.

  AQ4N [1,4-双[2-(二甲氨基-N-氧化物)乙基]氨基}-5,8-二羟基蒽-9,10-二酮]，一种具有两个二甲氨基N-氧化物基团的前药，被转化为拓扑异构酶 II 抑制剂 AQ4 [1,4-双[2-(二甲氨基)乙基]氨基}-5,8-二羟基-蒽-9,10-二酮]通过将 N-氧化物还原为二甲氨基取代基。早期研究表明，几种药物代谢细胞色素 P450 (P450) 酶可以在与实体瘤中类似的缺氧条件下催化这种还原反应。 CYP2S1和CYP2W1是从人类基因组中鉴定出的两种功能未知的肝外P450酶，它们在缺氧肿瘤细胞中的表达水平比正常组织中高得多。在这里，我们证明，与已发表的报告（Mol Pharmacol 76：1031-1043，2009）相反，CYP2S1 可以被 NADPH-P450 还原酶有效还原。最重要的是，与之前研究的所有 P450 酶相比，CYP2S1 和 CYP2W1 都是 AQ4N 还原活化为 AQ4 的更好催化剂。 CYP2S1和CYP2W1在肿瘤组织中的过度表达，以及它们对AQ4N激活的高催化活性，表明它们可用于抗癌前药的局部激活。