14-Hydroxy-3-((5-hydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate | 31087-94-2

• 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
• 英文名称: 14-Hydroxy-3-((5-hydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate
• 英文别名: [14-hydroxy-3-(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: 31087-94-2
• 化学式: C₃₂H₄₈O₉
• 分子量: 576.7
• InChiKey: JLPDBLFIVFSOCC-UHFFFAOYSA-N

物化性质

• 熔点：
  223-225 °C
• 沸点：
  693.7±55.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 颜色/状态：
  Crystals from ethanol
• 溶解度：
  In water, 1.557 mg/L at 25 °C (est)
• 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

• 毒性总结

鉴定和使用：阿兰定是一种固体。它是一种在植物Nerium oleander（普通夹竹桃）和Thevetia peruviana（黄花夹竹桃）中发现的强心苷。人类暴露和毒性：摄入阿兰定会导致恶心、呕吐、腹痛、腹泻、心律失常和高钾血症。在夹竹桃中毒的情况下，瞳孔散大通常伴随眩晕、抽搐、昏迷和心动过缓。意外摄入可能导致心脏心律失常甚至死亡。已经报道了几起致命和非致命中毒的案例。动物研究：在夹竹桃生长的地域，夹竹桃中毒应该是马科动物腹痛的鉴别诊断之一，特别是当同时检测到氮质血症或心脏心律失常时。生态毒性研究：对于淡水鱼C. punctatus来说，暴露于阿兰定的亚致死剂量24小时和96小时，会导致肝脏和肌肉组织中总蛋白、总游离氨基酸、核酸、糖原、丙酮酸、乳酸以及酶蛋白酶、磷酸酶、丙氨酸转氨酶、天冬氨酸转氨酶和乙酰胆碱酯酶活性的显著变化。

IDENTIFICATION AND USE: Oleandrin is a solid. It is a cardiac glycoside found in plants Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander). HUMAN EXPOSURE AND TOXICITY: Ingestion of either oleandrin results in nausea, vomiting, abdominal pain, diarrhea, dysrhythmias, and hyperkalemia. In poisoning by oleander, mydriasis characteristically accompanies vertigo, convulsions, coma, and bradycardia. Accidental ingestion can cause cardiac arrhythmias and even death. Several cases of fatal and non-fatal poisoning have been reported. ANIMAL STUDIES: Oleander intoxication should be a differential diagnosis for equids with colic in geographic areas where oleander is found, especially when azotemia or cardiac arrhythmias are detected concurrently. ECOTOXICITY STUDIES: For freshwater fish C. punctatus exposure to sub-lethal doses of oleandrin for 24 hr and 96 hr caused significant alteration in the level of total protein, total free amino acid, nucleic acid, glycogen, pyruvate, lactate and enzyme protease, phosphatases, alanine aminotransferase, aspartate aminotransferase and acetylcholinesterase activity in liver and muscle tissues.

来源:Hazardous Substances Data Bank (HSDB)

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性要低得多。例如，当无药物血清中加入10微克/毫升的夹竹桃苷时，我们观察到127.7纳克/毫升的地高辛当量，但仅2.4纳克/毫升的地高辛当量浓度。Digibind中和了所有研究的心脏毒素，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）的样本，在没有Digibind的情况下，自由浓度为14.5纳克/毫升地高辛当量，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）的样本中，在没有Digibind的情况下，自由浓度为8.6纳克/毫升，在存在100.0微克/毫升Digibind的情况下未检测到。因为这种中和作用也可能在体内发生，所以Digibind可能对治疗接触这些毒素的患者很有用。

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，以及中性粒细胞和巨噬细胞等不同细胞类型在这些过程中的参与，调节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，一种名为奥利安德林的心脏糖苷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。奥利安德林抑制了IL-8但不是TNF诱导的NF-κB依赖性基因表达。奥利安德林抑制了IL-8、EGF或NGF的结合，但不是IL-1或TNF。它在不改变对IL-8受体亲和力的同时，几乎减少了79%的IL-8结合，这种对IL-8结合的抑制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保护奥利安德林介导的IL-8结合抑制。磷脂显著保护了奥利安德林介导的IL-8结合抑制，从而恢复了IL-8诱导的NF-κB激活。奥利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，这是一种脂质结合荧光团。总的来说，我们的结果表明，奥利安德林通过改变膜流动性和微粘度来调节IL-8Rs，从而抑制了不同细胞类型中IL-8介导的生物学反应。这项研究可能有助于调节涉及炎症、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。夹竹桃的毒性源于夹竹桃苷及其苷元代谢物夹竹桃苷元。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有效成分，也推荐用于吸附胃肠道中的细菌毒素。Bio-Sponge已被用于预防家畜对夹竹桃毒素的胃肠道吸收，但活性炭和Bio-Sponge对吸附夹竹桃苷和夹竹桃苷元的有效性尚未研究。进行了一项体外实验，比较了三种市售吸附剂的效力。这些吸附剂包括Bio-Sponge、ToxiBan颗粒和一种普通等级的活性炭。ToxiBan颗粒具有最高的吸附能力，其次是普通等级的活性炭，最后是Bio-Sponge。Bio-Sponge没有吸附夹竹桃苷和夹竹桃苷元，这些物质在毒害动物胃肠道中的浓度预计会存在。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的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效的放射增敏剂。在当前研究中，我们探讨了奥利安德林这一心脏糖苷的相对放射增敏潜力，奥利安德林是一种包含在名为Anvirzel的植物提取物中的心脏病糖苷，最近作为抗癌治疗的新药完成了I期临床试验。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，增敏因子为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持续时间。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，效果显著增加。PC-3细胞对奥利安德林和辐射诱导的凋亡的易感性取决于caspase-3的激活。当细胞同时暴露于奥利安德林和辐射时，激活作用最大。使用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)

吸收、分配和排泄

(3)H奥利安德林是Anvirzel的心脏糖苷成分，对小鼠进行静脉注射（40微克/千克）或口服（80微克/千克）给药后的药物动力学研究。口服给药后，奥利安德林被迅速吸收（20分钟时达到Cmax），尽管消除半衰期比静脉给药长（2.3 +/- 0.5小时对0.4 +/- 0.1小时）。静脉给药和口服给药后得到的AUC0-无穷大值分别为24.6 +/- 11.1和14.4 +/- 4.3（纳克·小时/毫升），口服生物利用度大约为30%。静脉给药后，肝脏中的奥利安德林浓度是心脏或肾脏组织的两倍。在这些组织中还发现了奥利安德林的苷元奥利安德吉宁。在5分钟时，肝脏中总放射活性的> 60%归因于奥利安德林，而28%的给药量以奥利安德吉宁的形式存在。注射后24小时，8%的总放射活性随尿液排出，其中包含奥利安德吉宁（占注射剂量的4.4%）和奥利安德林（1.9%）。在粪便中发现了66%的注射放射活性，其中奥利安德林和奥利安德吉宁的含量相等。研究了奥利安德林在大脑中的摄取，通过腹腔注射奥利安德林（3毫克/千克）或夹竹桃提取物（700毫克/千克）。通过LC/MS/MS测量，注射提取物后大脑中的奥利安德林含量高于等效剂量的奥利安德林。数据显示，夹竹桃提取物中的成分可能增强奥利安德林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，而肺和大脑中则不含。

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)