geldanamycin hydroquinone | 169521-90-8

• 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: geldanamycin hydroquinone
• 英文别名: hydrogeldanamycin；geldanamycin, hydroquinone form；GMH2；17,21-dihydrogeldanamycin；B0X89M7X7M；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13,20,22-trihydroxy-8,14,19-trimethoxy-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: 169521-90-8
• 化学式: C₂₉H₄₂N₂O₉
• 分子量: 562.66
• InChiKey: PTPZSJCARURTEJ-KSRBKZBZSA-N

物化性质

• 沸点：
  791.2±60.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  170
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  geldanamycin hydroquinone 在 palladium 10% on activated carbon 作用下， 以 乙酸乙酯 为溶剂， 反应 0.33h， 以68%的产率得到格尔德霉素
  参考文献：
  名称：

  Total Synthesis of Geldanamycin

  摘要：

  DOI：

  10.1021/acs.joc.1c01582
• 作为产物：
  描述：

  格尔德霉素 在 recombinant human quinone oxidoreductase 1 、 还原型辅酶Ⅰ 、 bovine serum albumin 作用下， 反应 0.17h， 生成 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

文献信息

• [EN] GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS<br/>[FR] GELDANAMYCINE ET SES DERIVES POUVANT INHIBER UNE PROLIFERATION CANCEREUSE ET IDENTIFIER DE NOUVELLES CIBLES
  申请人：VAN ANDEL RES INST

  公开号：WO2005095347A1

  公开（公告）日：2005-10-13

  Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.

  盖尔达霉素衍生物可以在飞托摩尔浓度下阻断uPA-纤溶酶网络，抑制胶质母细胞瘤细胞和其他肿瘤的生长和侵袭，潜在地是高活性的抗癌药物。已披露了盖尔达霉素（GA）和各种17-氨基-17-去甲氧基盖尔达霉素衍生物，可以在飞托摩尔水平下阻断HGF/SF介导的Met酪氨酸激酶受体依赖的uPA激活。其他吖丝霉素类化合物（马克贝辛I和II）、盖尔达霉素衍生物和雷地可（radicicol）需要更高几个数量级（≥nM）的浓度才能实现这种抑制作用。经测试的化合物的抑制活性与该类药物已知结合到hsp90的能力不符，表明存在一种新的靶标，用于抑制HGF/SF介导的肿瘤发展事件。公开了使用这类化合物来抑制癌细胞活动和治疗肿瘤的方法。用这些高活性化合物的低剂量进行治疗为治疗各种表达Met的肿瘤提供了一种选择，特别是侵袭性脑癌，可以单独使用或与常规手术、化疗或放疗结合使用。
• Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and<i>Leishmania</i>Hsp90s
  作者：Sona Mohammadi-Ostad-Kalayeh、Frank Stahl、Thomas Scheper、Klaus Kock、Christian Herrmann、Fernanda Aparecida Heleno Batista、Júlio César Borges、Florenz Sasse、Simone Eichner、Jekaterina Ongouta、Carsten Zeilinger、Andreas Kirschning

  DOI：10.1002/cbic.201700616

  日期：2018.3.16

  Heat shock protein (Hsp) inhibition in parasites: New reblastatin derivatives, prepared by mutasynthesis complemented with a library of other Hsp inhibitors, were evaluated in cell‐based and in in vitro ATP displacement assays, the latter utilising purified human HsHsp90 and LbHsp90 from L. braziliensis. The study paves the way for finding selective inhibitors of parasitic heat shock proteins.

  寄生虫中的热休克蛋白（Hsp）抑制作用：通过诱变合成与其他Hsp抑制剂文库互补的新再生素衍生物，已在基于细胞的体外ATP置换测定中进行了评估，后者利用L纯化的人HsHsp90和LbHsp90 。braziliensis。该研究为寻找寄生性热激蛋白的选择性抑制剂铺平了道路。
• Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives
  作者：R. C. Schnur、M. L. Corman、R. J. Gallaschun、B. A. Cooper、M. F. Dee、J. L. Doty、M. L. Muzzi、J. D. Moyer、C. I. DiOrio

  DOI：10.1021/jm00019a010

  日期：1995.9

  The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.
• Total Synthesis of Geldanamycin
  作者：Zhi Zhang、Yunfeng Li、Rentao Zhang、Xiaoming Yu

  DOI：10.1021/acs.joc.1c01582

  日期：2021.11.5
• 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。