17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin

• 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: 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin
• 英文别名: 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]geldanamycin；17-(2-(pyrrolidin-1-yl)ethyl)amino-17-demethoxygeldanamycin；17-[2-(pyrrolidin-1-yl)ethyl]amino-17-demethoxygeldanamycin；17AEP-GA；(4e,6z,8s,9s,10e,12s,13r,14s,16r)-13-Hydroxy-8,14-Dimethoxy-4,10,12,16-Tetramethyl-3,20,22-Trioxo-19-{[2-(Pyrrolidin-1-Yl)ethyl]amino}-2-Azabicyclo[16.3.1]docosa-1(21),4,6,10,18-Pentaen-9-Yl Carbamate；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-(2-pyrrolidin-1-ylethylamino)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₃₄H₅₀N₄O₈
• 分子量: 642.793
• InChiKey: MNMYYWFEPBLDKF-JEVRCCDFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  170
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin 在 recombinant human quinone oxidoreductase 1 、 还原型辅酶Ⅰ 、 bovine serum albumin 作用下， 反应 0.17h， 生成 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin hydroquinone
  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
• 作为产物：
  描述：

  1-(2-氨乙基)吡咯烷 、 格尔德霉素 以 1,2-二氯乙烷 为溶剂， 反应 20.0h， 生成 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin
  参考文献：
  名称：

  Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

  摘要：

  Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.07.053

文献信息

• Synthesis and biological activities of novel 17-aminogeldanamycin derivatives
  作者：Zong-Qiang Tian、Yaoquan Liu、Dan Zhang、Zhan Wang、Steven D. Dong、Christopher W. Carreras、Yiqing Zhou、Giulio Rastelli、Daniel V. Santi、David C. Myles

  DOI：10.1016/j.bmc.2004.07.053

  日期：2004.10

  Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells. (C) 2004 Elsevier Ltd. All rights reserved.
• A Mechanistic and Structural Analysis of the Inhibition of the 90-kDa Heat Shock Protein by the Benzoquinone and Hydroquinone Ansamycins
  作者：Philip Reigan、David Siegel、Wenchang Guo、David Ross

  DOI：10.1124/mol.110.070086

  日期：2011.5

  The benzoquinone ansamycins inhibit the ATPase activity of the 90-kDa heat shock protein (Hsp90), disrupting the function of numerous client proteins involved in oncogenesis. In this study, we examine the role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the metabolism of trans - and cis -amide isomers of the benzoquinone ansamycins and their mechanism of Hsp90 inhibition. Inhibition of purified human Hsp90 by a series of benzoquinone ansamycins was examined in the presence and absence of NQO1, and their relative rate of NQO1-mediated reduction was determined. Computational-based molecular docking simulations indicated that the trans - but not the cis -amide isomers of the benzoquinone ansamycins could be accommodated by the NQO1 active site, and the ranking order of binding energies correlated with the relative reduction rate using purified human NQO1. The trans-cis isomerization of the benzoquinone ansamycins in Hsp90 inhibition has been disputed in recent reports. Previous computational studies have used the closed or cocrystallized Hsp90 structures in an attempt to explore this isomerization step; however, we have successfully docked both the trans - and cis -amide isomers of the benzoquinone ansamycins into the open Hsp90 structure. The results of these studies indicate that both trans - and cis -amide isomers of the hydroquinone ansamycins exhibited increased binding affinity for Hsp90 relative to their parent quinones. Our data support a mechanism in which trans - rather than cis -amide forms of benzoquinone ansamycins are metabolized by NQO1 to hydroquinone ansamycins and that Hsp90-mediated trans-cis isomerization via tautomerization plays an important role in subsequent Hsp90 inhibition.

  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。