17-((2-hydroxyethyl)amino)-17-demethoxygeldanamycin | 75758-38-2

• 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-((2-hydroxyethyl)amino)-17-demethoxygeldanamycin
• 英文别名: 17-HEA-DMGA；17-aminoethyl-hydroxyethylamino-17-demethoxygeldanamycin；17-hydroxyethylamino-17-dimethoxygeldanamycin；17-demethoxy-17-(2-hydroxyethylamino)geldanamycin；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-19-(2-hydroxyethylamino)-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• CAS: 75758-38-2
• 化学式: C₃₀H₄₃N₃O₉
• 分子量: 589.686
• InChiKey: IKFQBKKOFWMKDO-HSHPMGMFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  187
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  17-((2-hydroxyethyl)amino)-17-demethoxygeldanamycin 在 吡啶 、 盐酸羟胺 作用下， 反应 19.0h， 以47%的产率得到17-demethoxy-17-(2-hydroxyethylamino)geldanamycin-18-oxime
  参考文献：
  名称：

  WO2008/34895

  摘要：

  公开号：
• 作为产物：
  描述：

  17-(1-aziridinyl)-17-demethoxygeldanamycin 在 磷酸 、 水 作用下， 以 二甲基亚砜 为溶剂， 反应 2.0h， 以100%的产率得到17-((2-hydroxyethyl)amino)-17-demethoxygeldanamycin
  参考文献：
  名称：

  [EN] GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS
  [FR] GELDANAMYCINE ET SES DERIVES POUVANT INHIBER UNE PROLIFERATION CANCEREUSE ET IDENTIFIER DE NOUVELLES CIBLES

  摘要：

  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。

  公开号：

  WO2005095347A1

文献信息

• Micelle composition of polymer and passenger drug
  申请人：Kwon S. Glen

  公开号：US20060251710A1

  公开（公告）日：2006-11-09

  Hydrophobic drugs become more practical for treatments by being encapsulated in micelle compositions for increasing solubility. Micelle compositions may include an excipient tocopherol and/or prodrug formulations of the drug. Micelles extend the time period the drug remains in the micelles to improve drug circulation time and thereby drug delivery. Hydrophobic drugs for micelle encapsulation may include rapamycin, geldanamycin, and paclitaxel. Administration of these micelle compositions does not require Cremophor EL or Tween 80, avoiding serious side effects associated with these products which would previously accompany such drug administration.

  疏水药物通过封装在胶束组合物中增加溶解度，变得更加实用用于治疗。胶束组合物可能包括辅料生育酚和/或药物的前药配方。胶束延长药物在其中保持的时间，以改善药物循环时间，从而提高药物输送。用于胶束封装的疏水药物可能包括雷帕霉素、格兰达霉素和紫杉醇。这些胶束组合物的给药不需要克雷莫福尔EL或吐温80，避免了与这些产品相关的严重副作用，这些副作用以前会伴随着这种药物的给药。
• Drug and Imaging Agent Delivery Compositions and Methods
  申请人：UNIVERSITY OF KANSAS

  公开号：US20130189519A1

  公开（公告）日：2013-07-25

  A multi-arm, star-shaped polymer composition can be configured for drug delivery and imaging applications in vivo. The star polymer architecture can be synthesized using living radical polymerization techniques, including reversible addition-fragmentation chain transfer and macromolecular design via the interchange of xanthates with a broad range of reaction conditions and functional groups. The star-shaped polymeric carriers can be tailored for preferential delivery of chemotherapeutics into the tumor-draining lymphatics via subcutaneous, peritumoral or intratumoral injections. The carriers can be loaded with the chemotherapeutic agents from about 10% to about 25% w/w. In addition, the carriers can be loaded with imaging agents from about 5% to about 10% w/w. The molecular weights of the polymeric carriers can be about 40 kDa to about 130 kDa. The chemotherapeutics can be cisplatin, geldanamycin or nitric oxide-donating prodrugs. The imaging agent can be a near-infrared dye, such as IR820.

  一种多臂星形聚合物组合物可配置用于体内药物输送和成像应用。星形聚合物结构可以使用活性自由基聚合技术合成，包括可逆加成-断裂链转移和通过与广泛的反应条件和功能基团进行黄酮交换的宏观设计。星形聚合物载体可以定制为通过皮下、肿瘤周围或肿瘤内注射将化疗药物优先输送至肿瘤引流淋巴管。载体可以装载化疗药物，负载量约为10%至25%（重量/重量）。此外，载体可以装载成像剂，负载量约为5%至10%（重量/重量）。聚合物载体的分子量可以约为40 kDa至130 kDa。化疗药物可以是顺铂、吉尔达那霉素或一氧化氮供体前药。成像剂可以是近红外染料，如IR820。
• Synthesis, structure and anticancer activity of new geldanamycin amine analogs containing C(17)- or C(20)- flexible and rigid arms as well as closed or open ansa-bridges
  作者：Natalia Skrzypczak、Krystian Pyta、Piotr Ruszkowski、Maria Gdaniec、Franz Bartl、Piotr Przybylski

  DOI：10.1016/j.ejmech.2020.112624

  日期：2020.9

  nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin’s (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution

  胺的在C（17）或C（17）/ C的亲核攻击（20）格尔德霉素的（位置GDM）苯醌，经由初始1,4-迈克尔共轭加成机制，收率新类似物具有封闭或者打开的柄-bridges（1 - 31），分别。类似物的X射线结构22和24揭示了意想不到的排列柄-bridge在固体（构象异构体B）中，位于这些构象异构体A，在通行溶液（之间的反式β-内酰胺），和C，在关键结合Hsp90（顺式-内酰胺）。新型构象异构体B的结构可以更好地理解GDM类似物与目标Hsp90之间的分子识别机制。组合分析：抗癌测试结果（SKBR-3，SKOV-3，PC-3，U-87，A-549）和在正常细胞（HDF）中进行的测试，在Hsp90和c处的K D值和对接模式logP参数表明，具有H键受体作为羰基的C（17）刚性臂（哌啶基，环己基）和亲脂性clogP〜3有助于类似物的高效能，甚至在50到IC 50〜0.08μM与GDM相比，提高了选择性（SI
• Geldanamycin and Derivatives Inhibit Cancer Invasion and Identify Novel Targets
  申请人：Xie Qian

  公开号：US20070297980A1

  公开（公告）日：2007-12-27

  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.

  Geldanamycin衍生物可以阻断uPA-plasmin网络，抑制胶质母细胞瘤细胞和其他肿瘤的生长和侵袭，而且在飞阿托摩尔浓度下可能是高效的抗癌药物。GA和各种17-氨基-17-去甲基格尔达霉素衍生物被披露可在fM水平上阻断HGF/SF介导的Met酪氨酸激酶受体依赖的uPA激活。其他ansamycins（macbecins I和II）、GA衍生物和radicicol需要更高的浓度（≧nM）才能实现这种抑制。所测试的化合物的抑制活性与该类药物结合hsp90的已知能力不一致，表明在肿瘤发展中存在一种新的靶点（s）用于HGF/SF介导的事件。披露了使用这些化合物来抑制癌细胞活动和治疗肿瘤的方法。使用这些高效化合物的低剂量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，可以单独使用或与传统的手术、化疗或放疗联合使用。
• 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.