17-Azetidinyl-7-decarbamoyl-17-demethoxygeldanamycin | 155630-41-4

• 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-Azetidinyl-7-decarbamoyl-17-demethoxygeldanamycin
• 英文别名: 17-(1-azetidinyl)-7-decarbamyl-17-demethoxygeldanamycin；17-(1-azetidinyl)-7-decarbymyl-17-demethoxygeldanamycin；(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(azetidin-1-yl)-9,13-dihydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaene-3,20,22-trione
• CAS: 155630-41-4
• 化学式: C₃₀H₄₂N₂O₇
• 分子量: 542.673
• InChiKey: GSXQWUBWSJJTGO-APUTYTCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  39
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17-Azetidinyl-7-decarbamoyl-17-demethoxygeldanamycin 在 氨 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 50.0h， 生成 (4E,6Z,8S,9E,11S,12R,13R,14S,16R)-19-(azetidin-1-yl)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-11-sulfanyl-2-azabicyclo[16.3.1]docosa-1(21),4,6,9,18-pentaene-3,20,22-trione
  参考文献：
  名称：

  Tandem [3,3]-Sigmatropic Rearrangements in an Ansamycin: Stereospecific Conversion of an (S)-Allylic Alcohol to an (S)-Allylic Amine Derivative

  摘要：

  Ansamycin ring modifications in the geldanamycin oncogene inhibitor series were investigated. A carbamate to urea interchange was accomplished with net retention at the 7(S)-center of a geldanamycin analog. This chirally specific transformation was efficiently accomplished by employing tandem [3,3]-sigmatropic rearrangements involving first, the conversion of the allylic 7(S)-alcohol 2b to an allylic 9(S)-thiol, 4b, and then the rearrangement to the allylic 7(S)-isothiocyanate 6, which was carried on to allylic 7(S)-amine derivatives 1a and 1b. This tandem rearrangement strategy may have wide applicability for the preparation of chiral allylic amines from the large array of readily available chiral allylic alcohols.

  DOI：

  10.1021/jo00088a047
• 作为产物：
  描述：

  格尔德霉素 在 potassium tert-butylate 作用下， 以 二甲基亚砜 、 1,2-二氯乙烷 为溶剂， 生成 17-Azetidinyl-7-decarbamoyl-17-demethoxygeldanamycin
  参考文献：
  名称：

  Structure-based design of 7-carbamate analogs of geldanamycin

  摘要：

  The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl)amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.013

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。
• erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships
  作者：R. C. Schnur、M. L. Corman、R. J. Gallaschun、B. A. Cooper、M. F. Dee、J. L. Doty、M. L. Muzzi、C I. DiOrio、E. G. Barbacci

  DOI：10.1021/jm00019a011

  日期：1995.9

  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 ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated

  erbB-2癌基因的过度表达与乳腺癌，卵巢癌和胃癌的不良预后有关。人们发现，天然存在的苯并醌类安沙霉素抗生素除草霉素A，格尔德霉素（GDM）和二氢格尔德霉素会有效消耗培养的人乳腺癌SKBR-3细胞中的185 erbB-2癌蛋白p185。化学努力地选择性修饰GDM的ansa环，在体外和体内均提供了更高效能的衍生物。类似物证明，对带有人erbB-2转染的Fisher大鼠胚胎细胞的nu / nu裸鼠全身性给药后，在细胞培养物中和体内p185磷酸酪氨酸的抑制作用。ansa环中的官能团修饰是立体选择性和区域特异性的，无需保护策略。抗-erbB-2活性所需的基本官能团是7-氨基甲酸酯和2,3-双键。允许修改其他位置的官能团。描述了1-5、7-9、11、15和22取代的格尔德霉素的结构活性关系。
• Potent Cytotoxic C-11 Modified Geldanamycin Analogues
  作者：Zong-Qiang Tian、Zhan Wang、Karen S. MacMillan、Yiqing Zhou、Christopher W. Carreras、Thomas Mueller、David C. Myles、Yaoquan Liu

  DOI：10.1021/jm900098v

  日期：2009.5.28

  (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while

  17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）抑制Hsp90的活性，Hsp90是治疗癌症的重要靶标。为了鉴定性质优于17-AAG的格尔德霉素（GDM）类似物，我们合成了C-11修饰的GDM衍生物，包括醚，酯，氨基甲酸酯，酮和肟，并测量了它们对Hsp90的亲和力及其能力抑制人类癌细胞的生长。根据报道的GDM与Hsp90配合物的晶体结构，与C-11相连的庞大基团会干扰Hsp90的结合，而较小的基团（如11- O）-甲基允许Hsp90结合。另外，这些类似物还显示出对人癌细胞系的体外细胞毒性。17-AAG的11-OH的酯化消除了Hsp90的体外结合。在细胞毒性的测量过程中，易水解的酯起着前药的作用。因此，在这些实验期间，酯被水解，释放出17-AAG。鉴定了相对于17-AAG具有改善的效力的几种11 - O-甲基-17-烷基氨基格尔德霉素类似物。
• Geldanamycin derivatives and method of use thereof
  申请人：Wenkert David

  公开号：US20070207992A1

  公开（公告）日：2007-09-06

  The present invention relates to novel geldanamycin derivatives which have antitumor and antiparasitic properties. The geldanamycin derivatives disclosed herein have antitumor properties in humans due to their interaction with human heat shock protein 90 (hsp90). The human parasites Plasmodium falciparum, Trypanosoma Cruzi , and Leishmania donovani are lethally susceptible to exposure to geldanamycin via complexation of geldanamycin with their homologs (Pfhsp90, hsp83, and hsp90, respectively) of the human hsp90. The geldanamycin derivatives disclosed herein also interact with these parasitic hsp90 homologs so as to have antiparasitic properties.

  这项发明涉及具有抗肿瘤和抗寄生虫特性的新型格尔达霉素衍生物。本文披露的格尔达霉素衍生物由于与人类热休克蛋白90（hsp90）的相互作用而具有对人类的抗肿瘤特性。人类寄生虫疟原虫、克氏锥虫和唇形虫对格尔达霉素的暴露具有致命敏感性，通过格尔达霉素与它们的同源物（Pfhsp90、hsp83和hsp90，分别）形成络合物，这些同源物是人类hsp90的同源物。本文披露的格尔达霉素衍生物还与这些寄生虫hsp90同源物相互作用，具有抗寄生虫特性。
• Structure-based design of 7-carbamate analogs of geldanamycin
  作者：Giulio Rastelli、Zong-Qiang Tian、Zhan Wang、David Myles、Yaoquan Liu

  DOI：10.1016/j.bmcl.2005.08.013

  日期：2005.11

  The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl)amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive. (c) 2005 Elsevier Ltd. All rights reserved.