欧夹竹桃甙丙 | 465-16-7

• 物质功能分类: 生物化工 - 中草药成分
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 欧夹竹桃甙丙
• 中文别名: 欧夹竹桃苷；欧夹竹桃苷C；欧夹竹桃甙
• 英文名称: oleandrin
• 英文别名: O9640；[(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-[(2R,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-10,13-dimethyl-17-(5-oxo-2H-furan-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-16-yl] acetate
• CAS: 465-16-7
• 化学式: C₃₂H₄₈O₉
• 分子量: 576.728
• InChiKey: JLPDBLFIVFSOCC-XYXFTTADSA-N

物化性质

• 熔点：
  250°C
• 比旋光度：
  D25 -48.0° (c = 1.3 in methanol)
• 沸点：
  557.17°C (rough estimate)
• 密度：
  1.26
• 溶解度：
  DMF：15 mg/ml； DMF:PBS (pH 7.2) (1:4)：0.2 mg/ml； DMSO：10 mg/ml；乙醇：5 mg/ml
• 颜色/状态：
  Crystals from ethanol
• 蒸汽压力：
  3.61X10-19 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 旋光度：
  Specific optical rotation: -48.0 deg at 25 °C/D (c= 1.3 in methanol)
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.
• 解离常数：
  pKa1: 6.8 (carboxy); pKa2: 13.2 (hydroxy); pKa3: 14.1 (secondary hydroxy) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  9

ADMET

毒理性

• 相互作用

夹竹桃苷植物中毒在儿童中很常见，而且该植物提取物在中国医药中使用。其毒性主要是由夹竹桃苷和去糖基代谢物夹竹桃苷元引起的。蟾酥素和蟾酥总苷（蟾蜍心脏毒素）在中国医药中，如蟾酥、鹿肾五（Chan SU，和 Lu-Shen-WU）也广泛使用。食用蟾蜍汤后，蟾酥素引起的严重毒性已有报道。利用这些毒素与地高辛的结构相似性，我们证明了这些化合物可以通过荧光偏振免疫分析法快速地在血液中被检测出来。这些化合物与地高辛检测的交叉反应要低得多。例如，当不含药物的血清中加入10微克/毫升的夹竹桃苷时，我们观察到相当于127.7纳克/毫升的地高辛，但仅相当于2.4纳克/毫升的地高辛浓度。Digibind中和了我们研究中所有的心脏毒素，自由浓度显著下降。当含有50.0微克/毫升夹竹桃苷的血清池中加入0、10.0、25.0、50.0、100和200微克/毫升的Digibind时，平均自由浓度分别为30.6、23.3、16.0、10.7、7.8和5.5微克/毫升。同样，对于含有50.0微克/毫升夹竹桃苷元（总浓度：36.2纳克/毫升）的样品，在没有Digibind的情况下，自由浓度为14.5纳克/毫升地高辛当量，而在存在200微克/毫升Digibind的情况下为5.4纳克/毫升。在另一个含有500纳克/毫升蟾酥素（总浓度：156.9纳克/毫升）的标本中，在没有Digibind的情况下自由浓度为8.6纳克/毫升，而在存在100.0微克/毫升Digibind的情况下未检测到。因为这种中和也可能在体内发生，所以Digibind可能对治疗接触这些毒素的患者有用。

Oleandrin plant poisoning is common in children and the plant extract is used in Chinese medicines. The toxicity is due to oleandrin and the deglycosylated metabolite oleandrigenin. Bufalin and cinobufotalin (toad cardiac toxins) are also widely used in Chinese medicines like Chan SU, and Lu-Shen -WU. Severe toxicity from bufalin after consumption of toad soup has been reported. Taking advantage of structural similarities of these toxins with digitoxin, we demonstrated that these compounds can be rapidly detected in blood by the fluorescence polarization immunoassay for digitoxin. The cross reactivities of these compounds with digoxin assay were much lower. For example, when a drug free serum was supplemented with 10 ug/mL of oleandrin, we observed 127.7 ng/mL of digitoxin equivalent but only 2.4 ng/mL of digoxin equivalent concentration. Digibind neutralized all cardiac toxins studied as evidenced by significant fall of free concentrations. When aliquots of serum pool containing 50.0 ug/mL of oleandrin were supplemented with 0, 10.0, 25.0, 50.0, 100, and 200 ug/mL of digibind, the mean free concentrations were 30.6, 23.3, 16.0, 10.7, 7.8 and 5.5 ug/mL respectively. Similarly, with 50.0 ug/mL of oleandrigenin (total concentration: 36.2 ng/mL), the free concentration was 14.5 ng/mL digitoxin equivalent in the absence of digibind and 5.4 ng/mL in the presence of 200 microg/mL of digibind. In another specimen containing 500 ng/mL bufalin (total concentration: 156.9 ng/mL), the free concentration was 8.6 ng/mL in the absence of digibind and none detected in the presence of 100.0 ug/mL digibind. Because such neutralization may also occur in vivo, digibind may be useful in treating patients exposed to these toxins.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

考虑到白细胞介素-8（IL-8）在炎症、血管生成、肿瘤发生和转移中的潜在作用，以及特别是中性粒细胞和巨噬细胞在这些过程中的参与，调控IL-8介导的生物学反应是重要的。在本报告中，我们提供了证据表明，心脏糖苷素奥瑞安德林可能抑制了巨噬细胞中由IL-8、甲酰肽（FMLP）、表皮生长因子（EGF）或神经生长因子（NGF）但不是IL-1或肿瘤坏死因子（TNF）诱导的NF-κB激活。奥瑞安德林抑制了IL-8但不是TNF诱导的NF-κB依赖性基因表达。奥瑞安德林抑制了IL-8、EGF或NGF的结合，但不是IL-1或TNF的结合。它在不改变对IL-8受体的亲和力的同时，几乎减少了79%的IL-8结合，这种IL-8结合的抑制作用在分离的膜中被观察到。IL-8、抗IL-8Rs抗体或蛋白酶抑制剂无法阻止奥瑞安德林介导的IL-8结合抑制。磷脂显著保护了奥瑞安德林介导的IL-8结合抑制，从而恢复了IL-8诱导的NF-κB激活。奥瑞安德林改变了膜流动性，如通过微粘度参数检测到的那样，以及剂量依赖性地减少了二苯基己三烯，这是一种与脂质结合的荧光团。总的来说，我们的结果表明，奥瑞安德林通过改变膜流动性和微粘度来调节IL-8Rs，从而在不同细胞类型中抑制IL-8介导的生物学反应。这项研究可能有助于调控参与炎症、转移和新血管生成的IL-8介导的生物学反应。

Considering the potential role of interleukin-8 (IL-8) in inflammation, angiogenesis, tumorogenesis, and metastasis, and the involvement of different cell types especially neutrophils and macrophages in those processes, the regulation of IL-8-mediated biological responses is important. In this report we provide evidences that oleandrin, a cardiac glycoside potentially inhibited IL-8-, formyl peptide (FMLP)-, EGF-, or nerve growth factor (NGF)-, but not IL-1- or TNF-induced NF-kappaB activation in macrophages. Oleandrin inhibited IL-8-, but not TNF-induced NF-kappaB-dependent genes expression. Oleandrin inhibited the binding of IL-8, EGF, or NGF, but not IL-1 or TNF. It decreased almost 79% IL-8 binding without altering affinity towards IL-8 receptors and this inhibition of IL-8 binding was observed in isolated membrane. The IL-8, anti-IL-8Rs antibodies, or protease inhibitors were unable to protect oleandrin-mediated inhibition of IL-8 binding. Phospholipids significantly protected oleandrin-mediated inhibition of IL-8 binding thereby restoring IL-8-induced NF-kappaB activation. Oleandrin altered the membrane fluidity as detected by microviscosity parameter and a decrease in diphenylhexatriene, a lipid binding fluorophore binding in a dose-dependent manner. Overall, our results suggest that oleandrin inhibits IL-8-mediated biological responses in diverse cell types by modulating IL-8Rs through altering membrane fluidity and microviscosity. The study might help to regulate IL-8-mediated biological responses involved in inflammation, metastasis, and neovascularization.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

夹竹桃（Nerium oleander）中毒是全球许多地区常见的问题。夹竹桃的毒性源于oleandrin及其苷元代谢物oleandrigenin。活性炭是一种有用的胃肠道净化剂，可以限制摄入毒素的吸收。一种相对较新的粘土产品，Bio-Sponge，含有二-三-八面体蒙脱石作为活性成分，也推荐用于吸附胃肠道中的细菌毒素。Bio-Sponge已被用于防止家畜胃肠道吸收夹竹桃毒素，但活性炭和Bio-Sponge对吸附oleandrin和oleandrigenin的效果尚未研究。进行了一项体外实验，比较了三种市售吸附剂的效能。这些吸附剂包括Bio-Sponge、ToxiBan颗粒和一种普通等级的活性炭。ToxiBan颗粒的吸附能力最高，其次是普通等级的活性炭，最后是Bio-Sponge。Bio-Sponge没有吸附在预期会出现在中毒动物胃肠道中的oleandrin和oleandrigenin浓度。基于这项体外研究，含有活性炭的产品在绑定夹竹桃毒素和提供胃肠道净化方面比含有二-三-八面体蒙脱石的产品更有效。然而，这些吸附剂改变夹竹桃中毒动物或人类临床结果的能力还有待评估。

Oleander (Nerium oleander) poisoning is a common problem found in many parts of the world. The oleander toxicity is due to oleandrin and its aglycone metabolite oleandrigenin. Activated charcoal is a useful gastrointestinal decontamination agent that limits the absorption of ingested toxins. A relatively new clay product, Bio-Sponge, containing di-tri-octahedral smectite as the active ingredient, is also recommended for adsorbing bacterial toxins in the gastrointestinal tract. Bio-Sponge has been used to prevent gastrointestinal absorption of oleander toxins in livestock but the efficacy of activated charcoal and Bio-Sponge for adsorbing oleandrin and oleandrigenin has not yet been studied. An in vitro experiment to compare the efficacy of three commercially available adsorbents was performed. The adsorbents include Bio-Sponge, ToxiBan granules, and a generic grade activated charcoal. ToxiBan granules have the highest adsorptive capacity, followed by the generic grade activated charcoal, and finally, Bio-Sponge. Bio-Sponge did not adsorb oleandrin and oleandrigenin at concentrations that are expected to be present in the gastrointestinal tract of poisoned animals. On the basis of this in vitro study, products containing activated charcoal are more effective for binding oleander toxins and providing gastrointestinal decontamination than products containing di-tri-octahedral smectite. However, the ability of these adsorbents to alter the clinical outcome in oleander-poisoned animals or humans is yet to be evaluated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

心脏病糖苷类药物如洋地黄毒苷和乌本苷之前已被证明对肿瘤细胞具有选择性的细胞毒性，而不是正常细胞。此外，这类药物还被证明可以作为强烈的放射增敏剂。在当前研究中，我们探讨了奥利安德林这种心脏糖苷的相对放射增敏潜力，奥利安德林是一种包含在植物提取物Anvirzel中的心脏病糖苷，该提取物最近完成了一期作为新型抗癌治疗药物的试验。数据显示，奥利安德林增强了PC-3人前列腺细胞对辐射的敏感性；在细胞存活率为0.1时，增强因子为1.32。放射增敏的程度取决于细胞在辐射治疗前接触药物的时间长度。虽然奥利安德林在仅1小时的细胞药物接触后就显示出放射增敏效果，但在24小时药物预处理后，这种效果显著增加。PC-3细胞对奥利安德林和辐射诱导的细胞凋亡的易感性取决于caspase-3的激活。当细胞同时接触奥利安德林和辐射时，激活作用最大。用Z-DEVD-FMK抑制caspase-3的激活消除了奥利安德林增强辐射反应的效果，这表明奥利安德林和辐射在PC-3细胞系中共享一种依赖于caspase-3的细胞凋亡机制。

Cardiac glycosides such as digitoxin and ouabain have previously been shown to be selectively cytotoxic to tumor as opposed to normal cells. Moreover, this class of agents has also been shown to act as potent radiosensitizers. In the present study we explored the relative radiosensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzel that recently underwent a Phase I trial as a novel drug for anticancer therapy. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radiosensitization depended on duration of exposure of cells to drug prior to radiation treatment. While a radiosensitizing effect of oleandrin was evident with only 1 hr of cell exposure to drug, the effect greatly increased with 24 hr oleandrin pretreatment. Susceptibility of PC-3 cells to oleandrin and radiation-induced apoptosis was dependent on activation of caspase-3. Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

神经酰胺（N-乙酰-D-鞘氨醇），作为细胞信号传递的第二信使，能诱导转录因子，如核因子-κB（NF-κB）和激活蛋白-1（AP-1），并参与炎症和凋亡过程。能够抑制这些转录因子的物质可能能够阻止肿瘤发生和炎症。欧夹竹桃素（trans-3,4',5-三羟基芪），一种来自夹竹桃叶的多酚类心脏糖苷，多年来在俄罗斯和中国一直用于治疗心脏异常。我们研究了欧夹竹桃素对神经酰胺诱导的NF-κB和AP-1激活以及凋亡的影响。欧夹竹桃素阻断了神经酰胺诱导的NF-κB激活。欧夹竹桃素对NF-κB的抑制不仅限于人类上皮细胞；在人类淋巴样细胞、昆虫和小鼠巨噬细胞中也观察到了这种现象。NF-κB的抑制与AP-1的抑制相一致。欧夹竹桃素增强了神经酰胺诱导的活性中间产物生成、脂质过氧化、细胞毒性、胱天蛋白酶激活和DNA断裂。欧夹竹桃素在原代细胞中未表现出活性。因此，欧夹竹桃素的抗癌、抗炎和生长调节作用可能部分归因于其对NF-κB和AP-1激活的抑制以及凋亡的增强。

Ceramide (N-acetyl-D-sphingosine), a second messenger for cell signaling, induces transcription factors, like nuclear factor-kappa B (NF-kappa B), and activator protein-1 (AP-1) and is involved in inflammation and apoptosis. Agents that can suppress these transcription factors may be able to block tumorigenesis and inflammation. Oleandrin (trans-3,4',5-trihydroxystilbene), a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, has been used in the treatment of cardiac abnormalities in Russia and China for years. We investigated the effect of oleandrin on NF-kappa B and AP-1 activation and apoptosis induced by ceramide. Oleandrin blocked ceramide-induced NF-kappa B activation. Oleandrin-mediated suppression of NF-kappa B was not restricted to human epithelial cells; it was also observed in human lymphoid, insect, and murine macrophage cells. The suppression of NF-kappa B coincided with suppression of AP-1. Ceramide-induced reactive intermediates generation, lipid peroxidation, cytotoxicity, caspase activation, and DNA fragmentation were potentiated by oleandrin. Oleandrin did not show its activity in primary cells. Oleandrin's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappa B and AP-1 and potentiation of apoptosis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)Holeandrin 是 Anvirzel 的一个心脏糖苷成分。在小鼠中进行 (3)Holeandrin 的药代动力学研究，分别通过静脉注射（40ug/kg）和口服（80ug/kg）给药。口服给药后，oleandrin 迅速吸收（20分钟达到 Cmax），尽管消除半衰期较长（2.3 ± 0.5 小时），比静脉给药（0.4 ± 0.1 小时）要长。静脉和口服给药后获得的 AUC0-infinity 值分别为 24.6 ± 11.1 和 14.4 ± 4.3（ng·小时/mL），口服生物利用度大约为 30%。静脉给药后，肝脏中 oleandrin 的浓度是心脏或肾脏组织的两倍。在这些组织中还发现了 oleandrin 的苷元 oleandrigenin。在 5 分钟时，肝脏中总放射活性的> 60% 归因于 oleandrin，而给定剂量的 28% 作为 oleandrigenin 存在。注射后 24 小时，8% 的总放射活性通过尿液排出，其中包含 oleandrigenin（占注射剂量的 4.4%）和 oleandrin（1.9%）。66% 的注射放射性物质在粪便中发现，oleandrin 和 oleandrigenin 的含量相等。在大脑中摄入 oleandrin，在 oleandrin（3 mg/kg）或 oleander 提取物（700 mg/kg）的腹腔注射后进行了检查。通过 LC/MS/MS 测量，大脑中 oleandrin 的含量在注射提取物后比等效剂量的 oleandrin 要高。数据表明，oleander 提取物中的成分可能增强 oleandrin 穿过血脑屏障的转运。

Pharmacokinetic studies of (3)H oleandrin, a cardiac glycoside component of Anvirzel, were conducted in mice after either an i.v. dose (40 ug/kg) or a p.o. dose (80 ug/kg). Oleandrin was rapidly absorbed after oral dosing (Cmax at 20 min) although the elimination half-life was longer (2.3 +/- 0.5 hr) than that after i.v. dosing (0.4 +/- 0.1 hr). The AUC0-infinity values obtained after i.v. and p.o. dosing were 24.6 +/- 11.1 and 14.4 +/- 4.3 (ng.hr/mL), respectively, resulting in an oral bioavailability of approximately 30%. After i.v. administration, oleandrin concentration in liver was approximately twice that measured in heart or kidney tissue. Oleandrigenin, the aglycone of oleandrin, was also found in these tissues. At 5 min, > 60% of the total radioactivity in liver was due to oleandrin while 28% of the given dose was present as oleandrigenin. Twenty-four hours following injection, 8% of total radioactivity was excreted in urine and contained both oleandrigenin (4.4% of the injected dose) and oleandrin (1.9%). Sixty-six percent of injected radioactivity was found in feces and consisted of oleandrin and oleandrigenin in equal amounts. Uptake of oleandrin in brain after i.p. injection of oleandrin (3 mg/kg) or oleander extract (700 mg/kg) was examined. Measured by LC/MS/MS, oleandrin content in brain was higher following injection of extract than it was with an equivalent dose of oleandrin. The data suggest that components within oleander extract may enhance transport of oleandrin across the blood brain barrier.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

由于将夹竹桃进行煎剂或浸剂注入兔子体内所产生的毒性，被归因于各种器官中的夹竹桃苷含量。心脏、胃、肾脏和血液中含有最高的夹竹桃苷浓度，而肺和大脑中则没有。

The toxicity due to an infusion or decoction of N oleander into rabbits was attributed to the oleandrin content in various organs. The heart, stomach, kidneys, and blood contained the greatest oleandrin concentrations, whereas the lung and brain contained none.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S36/37/39,S45
• 危险类别码：
  R23/24/25
• WGK Germany：
  2,3