6,9,11-三羟基-9-(2-羟基乙酰基)-4-甲氧基-8,10-二氢-7H-并四苯-5,12-二酮 | 38554-25-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 并四苯
• 中文名称: 6,9,11-三羟基-9-(2-羟基乙酰基)-4-甲氧基-8,10-二氢-7H-并四苯-5,12-二酮
• 中文别名: 3β-羟基替勃龙
• 英文名称: Doxorubicin deoxyaglycone
• 英文别名: 7-deoxydoxorubicinolone；7-deoxydoxorubicinone；7-deoxyadriamycinone；7-Desoxy-adriamycinon；7-Deoxyadriamycinon；(9R)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 38554-25-5
• 化学式: C₂₁H₁₈O₈
• mdl: MFCD00871833
• 分子量: 398.369
• InChiKey: QHGFPRZWWKUHKF-OAQYLSRUSA-N

物化性质

• 熔点：
  >205°C (dec.)
• 沸点：
  742.7±60.0 °C(Predicted)
• 密度：
  1.587±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（轻微）、甲醇（轻微、加热、超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.285
• 拓扑面积：
  141
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6,9,11-三羟基-9-(2-羟基乙酰基)-4-甲氧基-8,10-二氢-7H-并四苯-5,12-二酮 在 过碘酸 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 2.25h， 生成 (5Z)-7-<((9R)-7,8,9,10-tetrahydro-6,9,11-trihydroxy-4-methoxy-5,12-dioxonaphthacene-9-carbonyl)oxy>-1-thia-5-cyclodecene-3,8-diyne
  参考文献：
  名称：

  Molecular Design, Chemical Synthesis, and Study of Novel Enediyne-Sulfide Systems Related to the Neocarzinostatin Chromophore

  摘要：

  The design and synthesis of the novel monocyclic enediyne-sulfide systems and their chemical and DNA cleavage properties are described. The parent enediyne-sulfide 6 possessing a hydroxy group at the allylic position was effectively synthesized via the cross-coupling of the cis-vinyl iodide 11 and the acetylene derivative 12 using a Pd(O)-Cu(I) catalyst and the cyclization reaction of the acyclic dibromide 20 employing sodium sulfide as the key steps. In addition, the esterifications of 6 using appropriate procedures provided a series of its simple derivatives 21-29 and the hybrids 38-44 containing naturally occurring intercalators, all of which are quite stable when handled at ambient temperature. The representative enediyne-sulfide 22 was smoothly aromatized by 1,8-diazabicyclo[5.4.0]undec-7-ene in cyclohexa-1,4-diene through radical pathways and by a hydroxy anion in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer through a polar pathway. Furthermore, it was clearly found that all enediyne-sulfides cleaved DNA under alkaline conditions without any additive and the hybrids 38 and 44, each of which has the aromatic moiety of the neocarzinostatin chromophore and manzamins, respectively, exhibited the strongest DNA cleaving abilities with the identical high purine base (G > A) selectivity.

  DOI：

  10.1021/ja00122a012
• 作为产物：
  描述：

  阿霉素 在 cytochrome P₄₅₀ reductase 、 human cardiovascular cytochrome P₄₅₀ CYP₂J₂ 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 aq. phosphate buffer 、 二甲基亚砜 为溶剂， 反应 0.17h， 生成 6,9,11-三羟基-9-(2-羟基乙酰基)-4-甲氧基-8,10-二氢-7H-并四苯-5,12-二酮
  参考文献：
  名称：

  Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin

  摘要：

  多柔比星（DOX）是一种用于治疗多种癌症的化疗药物。然而，它导致心脏毒性的部分原因是活性氧的形成。CYP2J2 是一种在心肌细胞中强表达的人类细胞色素 P450。它能将花生四烯酸（AA）转化为环二十碳三烯酸（EET）的四种不同的区域异构体。通过动力学分析，我们发现 CYP2J2 的 AA 代谢受 DOX 调节。我们发现细胞色素 P450 还原酶（CYP2J2 的氧化还原伙伴）将 DOX 代谢为 7-deoxydoxorubicin aglycone（7-de-aDOX）。这种代谢物随后与 CYP2J2 结合，抑制并改变 AA 的首选代谢位点，导致 EET 调节异构体的比例发生变化。此外，分子动力学模拟表明，7-de-aDOX 和 AA 可同时与 CYP2J2 活性位点结合，从而使 AA 的代谢位点发生变化。为了确定这些观察结果是否为 DOX/7-de-aDOX 所独有，我们使用了非心脏毒性 DOX 类似物--柔红霉素（Zorubicin，ZRN）和 5-iminodaunorubicin （5-IDN）。ZRN 和 5-IDN 可抑制 CYP2J2 介导的 AA 代谢，但不会改变 EET 区域异构体的比例。总之，我们证明 DOX 和 7-de-aDOX 可抑制 CYP2J2 介导的 AA 代谢，7-de-aDOX 与活性位点结合可改变具有心脏保护作用的 EET 的比例。这些对 CYP2J2 的机理研究有助于设计新的 DOX 替代衍生物。

  DOI：

  10.1021/acs.biochem.7b01025

文献信息

• DERIVATIVE OF STYRENE-MALEIC ACID COPOLYMER
  申请人：Maeda Hiroshi

  公开号：US20160317672A1

  公开（公告）日：2016-11-03

  The present invention provides a group of novel SMA derivatives and a covalent conjugate of the derivatives and an active substance. More specifically, the present invention provides: an SMA derivative which contains (i) a styrene-maleic acid copolymer (SMA) and (ii) a side chain (b) that contains a functional group (a) selected from among —NH2, —SH, —OH, —COOH, —NH—(C═NH)—NH 2 and —C(CH 2 —OH) 3 and introduced into a carboxyl group of a maleic acid residue of the SMA via an amide bond or an ester bond, and wherein when a plurality of side chain (b) is introduced into the SMA, the side chains (b) may be identical or different from each other; and a conjugate of this SMA derivative and an active substance.

  本发明提供了一组新型SMA衍生物以及这些衍生物和活性物质的共价结合物。具体来说，本发明提供了：一种包含（i）苯乙烯-马来酸共聚物（SMA）和（ii）含有从—NH2、—SH、—OH、—COOH、—NH—(C═NH)—NH2和—C(CH2—OH)3中选择的官能团（a）的侧链（b），并通过酰胺键或酯键引入到SMA的马来酸残基的羧基中的SMA衍生物，当引入多个侧链（b）到SMA中时，这些侧链（b）可以相同也可以不同；以及这种SMA衍生物和活性物质的共价结合物。
• Targeted Drug-Formaldehyde Conjugates and Methods of Making and Using the Same
  申请人：Koch H. Tad

  公开号：US20070275911A1

  公开（公告）日：2007-11-29

  The invention provides a prodrug platform technology for improving the therapeutic value of a variety of parent drug compounds by altering and improving drug characteristics such as aqueous solubility, hydrolytic stability, therapeutic index, toxicity profile, pharmacolcinetics and selectivity while allowing the potential for synthetic elaboration. The prodrug platform is particularly well suited for targeting therapeutic drugs, including anti-tumor drugs and antibiotics, to specific receptors on target cells (e.g., cancer cells and bacteria). The platform is a technology for providing an improved, preactivated form of a therapeutic drug, and for optionally targeting such drug to target cells or biological molecules. The invention is broadly applicable to many different therapeutic drugs, as well as to a variety of diseases and conditions, including a variety of forms of cancer and bacterial infections.

  本发明提供了一种前药平台技术，通过改变和改进药物特性，如水溶性、水解稳定性、治疗指数、毒性谱、药代动力学和选择性，从而提高各种原始药物化合物的治疗价值，同时允许潜在的合成扩展。该前药平台特别适用于将治疗药物，包括抗肿瘤药物和抗生素，定向靶向到目标细胞（例如癌细胞和细菌）上的特定受体。该平台是一种提供改进的、预激活形式的治疗药物的技术，并可选择性地将该药物定向到目标细胞或生物分子。本发明广泛适用于许多不同的治疗药物，以及多种癌症和细菌感染等不同疾病和病况。
• Enzyme-cleavable prodrug compounds
  申请人：Dubois Vincent

  公开号：US20090110753A1

  公开（公告）日：2009-04-30

  The prodrug of the invention is a modified form of a therapeutic agent and comprises a therapeutic agent, an oligopeptide, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by the enzyme Thimet oligopeptidase, or TOP. Also disclosed are methods of designing prodrugs by utilizing TOP-cleavable sequences within the conjugate and methods of treating patients with prodrugs of the invention.

  该发明的前药是治疗剂的改良形式，包括治疗剂、寡肽、稳定基团和可选的连接基团。该前药可被酶Thimet oligopeptidase（TOP）水解。还公开了利用共轭物中可被TOP水解的序列设计前药的方法以及利用该发明的前药治疗患者的方法。
• METHODS OF TREATING CANCER WITH DOXAZOLIDINE AND PRODRUGS THEREOF
  申请人：Koch Tad H.

  公开号：US20110135618A1

  公开（公告）日：2011-06-09

  The invention provides therapeutically effective compounds for the prevention and treatment of cancer and pharmaceutical compositions containing these compounds as well as methods of using and administering these compounds. The invention also includes methods of activating a prodrug of these therapeutically effective compounds by the administration of a peptide-directed targeting construct that delivers a prodrug-activating enzyme to a target activation site.

  本发明提供了预防和治疗癌症的治疗有效化合物，以及含有这些化合物的制药组合物，以及使用和管理这些化合物的方法。本发明还包括通过给靶向肽构造物输送一种前药激活酶到目标激活位点来激活这些治疗有效化合物的前药的方法。
• ALOE-EMODIN DERIVATIVES AND USE THEREOF FOR THE TREATMENT OF CANCER
  申请人：Fridman Micha

  公开号：US20130045933A1

  公开（公告）日：2013-02-21

  The present invention relates to anthracycline derivatives that are based on an Aloe-emodin (AE) backbone attached to a glycoside (an amino sugar or amino carba-sugar). These derivatives are useful as chemotherapeutic agents. Advantageously, these derivatives are potent cytotoxic agents against a variety of anthracycline-resistant tumors. In addition, they may have reduced cardiotoxicity. As such, the novel compounds of the invention offer an advantage over currently available drugs. The present invention further relates to methods for preparing the novel Aloe-Emodin Glycoside (AEG) based derivatives, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as chemotherapeutic agents for prevention and treatment of cancers.

  本发明涉及基于芦荟大黄素（AE）骨架与糖苷（氨基糖或氨基卡巴糖）相连的蒽环类衍生物，这些衍生物可用作化疗药物。这些衍生物对多种蒽环类耐药肿瘤具有强效的细胞毒性作用。此外，它们可能具有较低的心脏毒性。因此，本发明的新化合物比目前可用的药物具有优势。本发明还涉及制备新的芦荟大黄素糖苷（AEG）衍生物的方法，包括这些化合物的制药组合物，以及使用这些化合物和组合物的方法，特别是作为预防和治疗癌症的化疗药物。