18,21-dihydro-17-amino-17-demethoxygeldanamycin | 574718-86-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 18,21-dihydro-17-amino-17-demethoxygeldanamycin
• 英文别名: 17-(amino)-17-demethoxygeldanamycin hydroquinone；17AGH2；18,21-dihydro-17-aminogeldanamycin；17-amino-17-demethoxy-18,21-dihydroxy-geldanamycin；17-aminogeldanamycin hydroquinone；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-amino-13,20,22-trihydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3-oxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18(22),19-hexaen-9-yl] carbamate
• CAS: 574718-86-8
• 化学式: C₂₈H₄₁N₃O₈
• 分子量: 547.649
• InChiKey: OLZVLNRBIKBPIX-TWNAANEASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  39
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  187
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  18,21-dihydro-17-amino-17-demethoxygeldanamycin 在 air 、 copper(II) sulfate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 15.0h， 生成 17-acetylamino-17-demethoxygeldanamycin
  参考文献：
  名称：

  Synthesis and Biological Evaluation of a New Class of Geldanamycin Derivatives as Potent Inhibitors of Hsp90

  摘要：

  The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt; followed by their proteasomal degradation. Rsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage For cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft; models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and areas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.

  DOI：

  10.1021/jm0306125
• 作为产物：
  描述：

  17-amino-17-demethoxygeldanamycin 在 recombinant human quinone oxidoreductase 1 、 还原型辅酶Ⅰ 、 bovine serum albumin 作用下， 反应 0.17h， 生成 18,21-dihydro-17-amino-17-demethoxygeldanamycin
  参考文献：
  名称：

  A Mechanistic and Structural Analysis of the Inhibition of the 90-kDa Heat Shock Protein by the Benzoquinone and Hydroquinone Ansamycins

  摘要：

  苯醌类ansamycins抑制90-kDa热休克蛋白（Hsp90）的ATP酶活性，从而破坏了许多参与肿瘤发生的客户蛋白的功能。在这项研究中，我们考察了 NAD(P)H:quinone 氧化还原酶 1 (NQO1) 在苯醌ansamycins 的反式和顺式酰胺异构体代谢中的作用及其抑制 Hsp90 的机制。在 NQO1 存在和不存在的情况下，考察了一系列苯醌ansamycins 对纯化的人 Hsp90 的抑制作用，并测定了它们在 NQO1 介导下的相对还原率。基于计算的分子对接模拟表明，NQO1 活性位点可以容纳苯醌ansamycins 的反式（而非顺式）酰胺异构体，并且结合能的排序与使用纯化的人类 NQO1 的相对还原率相关。最近的报告对苯醌ansamycins在抑制Hsp90过程中的反式-顺式异构化提出了争议。以前的计算研究使用封闭的或共晶的 Hsp90 结构来尝试探索这一异构化步骤；然而，我们已经成功地将苯醌ansamycins 的反式和顺式酰胺异构体对接到开放的 Hsp90 结构中。这些研究结果表明，与母体醌类化合物相比，反式和顺式苯醌氨酰胺异构体与 Hsp90 的结合亲和力都有所提高。我们的数据支持这样一种机制，即苯醌氨酪酸的反式而非顺式酰胺形式通过 NQO1 代谢为对苯二酚氨酪酸，而 Hsp90 介导的反式-顺式异构体通过同分异构在随后的 Hsp90 抑制中发挥重要作用。

  DOI：

  10.1124/mol.110.070086

文献信息

• Hydroquinone Ansamycin Formulations
  申请人：Wright James L.

  公开号：US20080255080A1

  公开（公告）日：2008-10-16

  Pharmaceutical compositions of hydroquinone geldanamycin analogs, and uses of such compositions, are provided.

  提供了羟基喹啉格氨环素类似物的药物组合物，以及这种组合物的用途。
• Phospholipid-based pharmaceutical formulations and methods for producing and using same
  申请人：Ulm H. Edgar

  公开号：US20060228405A1

  公开（公告）日：2006-10-12

  Pharmaceutical formulations and methods of producing and using the same are described and claimed. The formulations are dispersions of phospholipids and one or more pharmacologically active compounds, pharmaceutically acceptable salts thereof, or prodrugs thereof. In specific embodiments, the pharmaceutically active compounds are ansamycins and the overall formulation is substantially devoid of medium and long chain triglycerides.

  药物配方及其生产和使用方法已被描述和声明。这些配方是磷脂和一个或多个药理活性化合物、其药学上可接受的盐或其前药的分散体。在具体实施中，药理活性化合物是ansamycins，整体配方基本上不含中长链甘油三酯。
• [EN] ANSAMYCIN HYDROQUINONE COMPOSITIONS<br/>[FR] COMPOSITIONS D'ANSAMYCINE HYDROQUINONE
  申请人：INFINITY DISCOVERY INC

  公开号：WO2010045442A1

  公开（公告）日：2010-04-22

  Aspects of the present invention provide compositions comprising a sulfur containing compound and a compound of the formula (I); and also provide methods of their preparation and use.

  本发明的方面提供了一种包含含硫化合物和式(I)化合物的组合物，以及它们的制备和使用方法。
• ANALOGS OF BENZOQUINONE-CONTAINING ANSAMYCINS AND METHODS OF USE THEREOF
  申请人：Adams Julian

  公开号：US20090253653A1

  公开（公告）日：2009-10-08

  The present invention provides analogs of benzoquinone-containing ansamycins and uses thereof for treating and modulating disorders associated with hyperproliferation, such as cancer. The present invention provides analogs of benzoquinone-containing ansamycins where the benzoquinone is reduced to a hydroquinone and trapped by reaction with a suitable acid, preferably ones that increase the solubility and air stability of the resulting 17-ammonium hydroquinone ansamycin analog.

  本发明提供了苯醌含有的ansamycins的类似物及其用于治疗和调节与高增殖相关的疾病，如癌症。本发明提供了苯醌含有的ansamycins的类似物，其中苯醌被还原为氢醌，并通过与适当酸反应被固定，优选那些增加所得到的17-铵氢醌ansamycin类似物的溶解度和空气稳定性的酸。
• Analogs of Benzoquinone-Containing Ansamycins and Methods of Use Thereof
  申请人：Adams Julian

  公开号：US20090062250A1

  公开（公告）日：2009-03-05

  The present invention provides analogs of benzoquinone-containing ansamycins and uses thereof for treating and modulating disorders associated with hyperproliferation, such as cancer. The present invention provides analogs of benzoquinone-containing ansamycins where the benzoquinone is reduced to a hydroquinone and trapped by reaction with a suitable acid, preferably ones that increase the solubility and air stability of the resulting 17-ammonium hydroquinone ansamycin analog.

  本发明提供了苯醌含量的ansamycins的类似物及其用于治疗和调节与过度增殖有关的疾病，如癌症。本发明提供了苯醌含量的ansamycins的类似物，其中苯醌被还原为一个氢醌，并通过与适当酸的反应被固定，优选增加所得到的17-铵盐氢醌ansamycin类似物的溶解性和空气稳定性的酸。