阿螺旋霉素 | 467214-20-6

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 中文名称: 阿螺旋霉素
• 中文别名: 17-[2-(二甲基氨基)乙基氨基]-17-去甲基格尔德霉素
• 英文名称: alvespimycin
• 英文别名: 17-demethoxy-17-[[2-(dimethylamino)ethyl]amino]-geldanamycin；17-demethoxy-17-[[2-(dimethylamino)ethyl]amino]geldanamycin；17-[2-(dimethylamino)ethyl]amino-17-demethoxygeldanamycin；17-{[(dimethylamino)ethyl]amino}-17-demethoxygeldanamycin；17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin；17-(2-dimethylaminoethylamino)-17-demethoxygeldanamycin；[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-[2-(dimethylamino)ethylamino]-13-hydroxy-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: 467214-20-6
• 化学式: C₃₂H₄₈N₄O₈
• 分子量: 616.755
• InChiKey: KUFRQPKVAWMTJO-LMZWQJSESA-N

物化性质

• 熔点：
  >270°C (dec.)
• 沸点：
  810.5±65.0 °C(Predicted)
• 密度：
  1.20
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  170
• 氢给体数：
  4
• 氢受体数：
  10

ADMET

代谢

Alvespimycin在纯化的人细胞色素P450还原酶（CYP3A4/3A5）催化下展现氧化还原循环，形成醌和氢醌。它还能够在醌环的19位形成谷胱甘肽结合物。然而，体内和体外研究显示，Alvespimycin在人体内代谢较弱。

Alvespimycin demonstrates redox cycling catalyzed by purified human cytochrome P450 reductase (CYP3A4/3A5) to quinones and hydroquinones. It could also form glutathione conjugates at the 19-position on the quinone ring. However in vivo and in vitro studies suggest that weak metabolism of alvespimysin occurs in humans.

来源:DrugBank

毒理性

• 蛋白质结合

据报道，影响很小。

Reported to be minimal.

来源:DrugBank

吸收、分配和排泄

• 吸收

药物浓度的增加导致血浆浓度与剂量成正比增加。在最大耐受剂量80mg/m^2下，所有患者的血浆浓度在不到24小时内超过了63nM（17-DMAG在NCI 60人肿瘤细胞系面板中的平均IC50值）。在这个剂量下，平均峰浓度（Cmax）达到了2680 nmol/L。

Increasing concentration of the drug results in dose-proportional increase in the plasma concentration. At the maximum tolerated dose of 80mg/m^2, the plasma concentration exceeded 63nM (mean IC50 for 17-DMAG in the NCI 60 human tumor cell line panel) for less than 24 hours in all patients. The mean peak concentration (Cmax) reached 2680 nmol/L at this dose.

来源:DrugBank

吸收、分配和排泄

• 排除途径

主要是肾脏和胆汁排泄途径。在一项小鼠研究中，给药后24小时收集的尿液中回收了10.6-14.8%的未改变给药剂量。

Mainly renal and biliary elimination pathways. In a mice study, the excreted urine 24 hours post-dose recovered 10.6–14.8% of delivered dose unchanged.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在最大耐受剂量80mg/m^2下，平均分布容积Vd值为385升。

At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L.

来源:DrugBank

吸收、分配和排泄

• 清除

平均清除率为18.9升/小时，在80毫克/平方米剂量的情况下。

The mean clearance is 18.9 L/hr at the dose of 80mg/m^2.

来源:DrugBank

安全信息

• 海关编码：
  29419090
• 储存条件：
  -20°C

制备方法与用途

简介

阿螺旋霉素Alvespimycin是一种有效的Hsp90抑制剂。

用途

阿螺旋霉素能够抑制Hsp90和Her2的表达，从而导致肿瘤细胞凋亡。

应用

作为一种科研试剂，阿螺旋霉素广泛应用于分子生物学、药理学等领域。请注意，严禁将其用于人体。

反应信息

• 作为反应物：
  描述：

  阿螺旋霉素 在 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 为溶剂， 以135 mg的产率得到17-[2-(dimethylamino)ethylamino]-11-oxo-17-demethyoxygeldanamycin
  参考文献：
  名称：

  强大的细胞毒性C-11修饰格尔德霉素类似物

  摘要：

  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。

  DOI：

  10.1021/jm900098v
• 作为产物：
  描述：

  N,N-二甲基乙二胺 、 格尔德霉素 以 1,2-二氯乙烷 为溶剂， 生成 阿螺旋霉素
  参考文献：
  名称：

  Geldanamycin compounds and method of use

  摘要：

  具有I式结构的Geldanamycin化合物，其中Q1、L、L1、R5、R6和R11的定义如本文所述，可用于治疗通过抑制细胞外热休克蛋白90的功能而改善的疾病或疾病。

  公开号：

  US20050267046A1

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。
• Redox Properties and Thiol Reactivity of Geldanamycin and its Analogues in Aqueous Solutions
  作者：Amram Samuni、Sara Goldstein

  DOI：10.1021/jp304206n

  日期：2012.6.7

  which correlates with the order of the redox potential of the quinone/semiquinone couple. Thus, GM reacts much faster with thiols compared to the less toxic 17-DMAG and 17-AAG, and is also expected to be more readily reduced by reductases to the respective semiquinone radical, which either decomposes to yield the respective hydroquinone or reduces oxygen to superoxide. Because both redox cycling and thiol

  格尔德霉素（GM）是苯醌安沙霉素抗生素，是Hsp90的天然产物抑制剂，具有强效和广泛的抗癌特性，但肝毒性水平不可接受。已经合成了毒性较小的C17-取代的类似物，包括17-（烯丙基氨基）-17-脱甲氧基格尔德霉素（17-AAG）和水溶性17-（二甲基氨基乙基氨基）-17-脱甲氧基格尔德霉素（17-DMAG）。氧化还原特性和硫醇反应性是醌的治疗和毒理学作用的关键，并且由于GM，17-AAG和17-DMAG的毒性程度是否与其氧化还原电位有关而引起了问题。使用脉冲辐射分解法，已确定GM和17-AAG在pH 7.0时的单电子氧化还原电势（vs NHE）分别为-62±7 mV和-273±8 mV，而其值为-194±6 mV先前已针对17-DMAG发布。在pH 7.4的缺氧条件下，GM及其类似物与谷胱甘肽，半胱氨酸或二硫苏糖醇的反应速率常数遵循GM> 17-DMAG> 17-AAG的顺序，这与醌/半醌的
• Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90
  作者：Russell R. A. Kitson、Chuan-Hsin Chang、Rui Xiong、Huw E. L. Williams、Adrienne L. Davis、William Lewis、Donna L. Dehn、David Siegel、S. Mark Roe、Chrisostomos Prodromou、David Ross、Christopher J. Moody

  DOI：10.1038/nchem.1596

  日期：2013.4

  The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases. The heat shock protein Hsp90 is a potential target for cancer and neurodegeneration drugs. Here, the introduction of a substituent into the 19-position of the naturally occurring inhibitor geldanamycin by chemical synthesis is shown to ameliorate toxicity, and also cause a favourable conformational switch that is required for protein binding.

  苯醌类的安赛蜜（geldanamycin）及其衍生物是热休克蛋白Hsp90的抑制剂，Hsp90是癌症和神经退行性疾病中新兴的治疗靶点。然而，这些化合物对正常细胞的毒性被归因于它们与醇类亲核试剂在醌的19位点反应。我们推测，封闭该位置将减轻毒性，同时也可能促使反式酰胺基团转变为蛋白质结合所需的顺式结构。在这里，我们报告了这种19取代化合物的高效合成及我们假设的实现。蛋白质晶体学表明，新化合物与Hsp90结合时，确实呈现出顺式酰胺构象。对细胞中Hsp90抑制的研究展示了Hsp90抑制剂的分子特征：在人体乳腺癌和多巴胺能神经细胞中，客户蛋白减少，其他热休克蛋白相应增加，显示出它们在癌症或神经退行性疾病治疗中的潜力。热休克蛋白Hsp90是癌症和神经退行性药物的潜在靶点。在这里，化学合成将在天然抑制剂安赛蜜的19位引入取代基，显示出减轻毒性，并促使所需的蛋白质结合顺式构象的有利转变。
• In Vitro Metabolism of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin in Human Liver Microsomes
  作者：Nan Zheng、Peng Zou、Shaomeng Wang、Duxin Sun

  DOI：10.1124/dmd.110.036418

  日期：2011.4

  The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.

  本研究旨在探讨17-(二甲基氨基乙氨基)-17-去甲氧基格尔德霉素(17-DMAG)的氧化代谢途径，该物质是一种格尔德霉素(GA)衍生物及90 kDa热休克蛋白抑制剂。通过使用人肝微粒体(HLMs)和重组CYP450同工酶，在有无还原型谷胱甘肽(GSH)的存在下，对17-DMAG的体外代谢谱进行了研究。除了17-DMAG氢醌和19-谷胱甘肽17-DMAG外，通过液相色谱-串联质谱法检测并鉴定了17-DMAG的几种氧化代谢物。与先前报道的GA和GA衍生物的主要生物转化方式不同，17-DMAG在HLMs中并非主要通过苯醌还原和GSH结合进行代谢。相反，17-DMAG在HLMs中的主要生物转化方式是其侧链的羟基化和去甲基化。最丰富的代谢物是由12位甲氧基的去甲基化产生的。反应表型研究显示，CYP3A4和3A5是参与17-DMAG氧化代谢的主要细胞色素P450同工酶，而CYP2C8、2D6、2A6、2C19和1A2对代谢物的形成贡献较小。基于所识别的代谢物谱，提出了17-DMAG在HLMs中的生物转化途径。
• 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。