(2S)-2-[(2R,5S,6R)-6-[(2S,3S,4S,6R)-6-[(3S,5S,7R,9S,10S,12R,15R)-3-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyloxan-2-yl]-15-hydroxy-3,10,12-trimethyl-4,6,8-trioxadispiro[4.1.57.35]pentadec-13-en-9-yl]-3-hydroxy-4-methyl-5-oxooctan-2-yl]-5-methyloxan-2-yl]butanoic acid | 53003-10-4

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗原虫药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (2S)-2-[(2R,5S,6R)-6-[(2S,3S,4S,6R)-6-[(3S,5S,7R,9S,10S,12R,15R)-3-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyloxan-2-yl]-15-hydroxy-3,10,12-trimethyl-4,6,8-trioxadispiro[4.1.57.35]pentadec-13-en-9-yl]-3-hydroxy-4-methyl-5-oxooctan-2-yl]-5-methyloxan-2-yl]butanoic acid
• CAS: 53003-10-4
• 化学式: C₄₂H₇₀O₁₁
• 分子量: 751.0
• InChiKey: KQXDHUJYNAXLNZ-HAXOTRLASA-N

物化性质

• 熔点：
  112.5-113.5 °C(lit.)
• 比旋光度：
  D25 -63° (c = 1 in ethanol)
• 沸点：
  839.2±65.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 闪点：
  >110°(230°F)
• 溶解度：
  不溶于水；乙醇中≥142.2 mg/mL； DMSO 中≥91.8 mg/mL
• LogP：
  5.596 (est)
• 蒸汽压力：
  6.37X10-23 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 旋光度：
  Specific optical rotation = -63 deg at 25 °C/D (sodium) line (c = 1 in ethanol)
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.
• 解离常数：
  pKa = 4.5 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  53
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  161
• 氢给体数：
  4
• 氢受体数：
  11

ADMET

代谢

... 马度米星（SAL），一种广谱抗生素和球虫抑制剂，被发现比现有的化疗药物（如紫杉醇和阿霉素）更有效地对抗肿瘤耐药性和杀死癌症干细胞；这重新聚焦了它对人类癌症治疗的重要性。在这项研究中，我们研究了SAL的体外药物代谢和药代动力学参数。SAL在肝脏微粒体中迅速代谢，具有高内源性清除率。SAL的代谢主要由CYP酶介导；CYP3A4是主要的代谢SAL的酶。与小鼠和大鼠血浆相比，SAL在人血浆中的血浆蛋白结合率显著较低。通过化学抑制和重组酶研究进行了CYP抑制。发现SAL是CYP2D6以及CYP3A4的中等抑制剂。由于CYP3A4是主要负责SAL代谢的酶，因此在 rats 中进行了药代动力学研究，以检查同时给予酮康唑（KTC）对SAL药代动力学的影响。KTC作为一种选择性的CYP3A4抑制剂，在同时给予KTC的大鼠中，显著增加了SAL的系统暴露量，AUC0-a增加了7倍，Cmax增加了3倍。

... Salinomycin (SAL), a broad spectrum antibiotic and a coccidiostat has been found to counter tumour resistance and kill cancer stem cells with better efficacy than the existing chemotherapeutic agents; paclitaxel and doxorubicin. This refocused its importance for treatment of human cancers. In this study, we studied the in vitro drug metabolism and pharmacokinetic parameters of SAL. SAL undergoes rapid metabolism in liver microsomes and has a high intrinsic clearance. SAL metabolism is mainly mediated by CYP enzymes; CYP3A4 the major enzyme metabolising SAL. The percent plasma protein binding of SAL in human was significantly lower as compared to mouse and rat plasma. CYP inhibition was carried out by chemical inhibition and recombinant enzyme studies. SAL was found to be a moderate inhibitor of CYP2D6 as well as CYP3A4. As CYP3A4 was the major enzyme responsible for metabolism of SAL, in vivo pharmacokinetic study in rats was done to check the effect of concomitant administration of Ketoconazole (KTC) on SAL pharmacokinetics. KTC, being a selective CYP3A4 inhibitor increased the systemic exposure of SAL significantly to 7-fold in AUC0-a and 3-fold increase in Cmax of SAL in rats with concomitant KTC administration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

肝细胞癌（HCC）是少数几种在过去几年中观察到发病率持续增加的癌症之一。耐药性是治疗HCC的一个主要问题。在当前研究中，我们使用Salinomycin（Sal）和5-氟尿嘧啶（5-FU）联合疗法对HCC细胞系Huh7、LM3和SMMC-7721以及裸鼠皮下肿瘤模型进行研究，以探究Sal是否能增加肝癌细胞对传统化疗药物如5-FU的敏感性。Sal和5-FU的联合使用在体内外对肝肿瘤产生了协同的抗肿瘤效果。Sal逆转了5-FU诱导的CD133(+) EPCAM(+)细胞增加、上皮-间质转化以及Wnt/β-连环蛋白信号通路的激活。Sal和5-FU的联合可能为我们提供了一种新的方法，用于逆转HCC患者的药物耐药性治疗。

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continuous increase in incidence has been observed over several years. Drug resistance is a major problem in the treatment of HCC. In the present study, we used salinomycin (Sal) and 5-fluorouracil (5-FU) combination therapy on HCC cell lines Huh7, LM3 and SMMC-7721 and nude mice subcutaneously tumor model to study whether Sal could increase the sensitivity of hepatoma cells to the traditional chemotherapeutic agent such as 5-FU. The combination of Sal and 5-FU resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. Sal reversed the 5-FU-induced increase in CD133(+) EPCAM(+) cells, epithelial-mesenchymal transition and activation of the Wnt/beta-catenin signaling pathway. The combination of Sal and 5-FU may provide us with a new approach to reverse drug resistant for the treatment of patients with HCC.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

化疗治疗软组织肉瘤的效果仍然不理想，因为它们的化疗敏感性较低。即便是第一线化疗药物多柔比星（doxorubicin），其响应率也只有18-29%。最近的研究表明，抗生素萨利诺霉素（salinomycin），一种钾离子载体，是一种强大的化合物，能够耗尽像腺癌中的癌症干细胞（CSC）这样的化疗耐药细胞。在这里，我们评估了萨利诺霉素对肉瘤细胞系的影响，分析了萨利诺霉素单独治疗以及与多柔比星联合治疗方案的疗效。为了评估萨利诺霉素对纤维肉瘤、横纹肌肉瘤和脂肪肉瘤细胞系的影响，细胞分别接受单一和联合治疗。通过细胞活力分析、细胞周期分析、caspase 3/7和9活性分析来监测相应治疗的效果。此外，我们还分析了NF-kappaB活性；p53、p21和PUMA的转录水平，以及p53表达和丝氨酸15磷酸化。萨利诺霉素与多柔比星的联合使用增强了caspase的激活并增加了亚G1期细胞的比例。联合治疗导致了更高的NF-kappaB活性，以及p53、p21和PUMA的转录水平，而萨利诺霉素单独治疗没有引起任何显著变化。萨利诺霉素增加了肉瘤细胞系对细胞毒性药物多柔比星的化疗敏感性——即使在亚致死浓度下也是如此。这些发现支持了一种策略，即在联合使用萨利诺霉素的情况下减少多柔比星的浓度，以减少毒性副作用。

Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed. To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-kappaB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation. The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-kappaB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes. Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一个因子设计（2x3）被用来评估黄曲霉毒素（0、2.5和5毫克每千克）和盐霉素（1、60克每吨（909千克））之间的相互作用。每个处理有四组重复，每组10只小鸡。...在所测量的任何参数上，黄曲霉毒素和盐霉素之间没有观察到显著的相互作用。

A factorial design (2 by 3) was used to evaluate the interaction between aflatoxin (0, 2.5, & 5 mg per kg) & salinomycin (1, 60 g per ton (909 kg)). There were four replicates of 10 chicks per treatment. ... No significant interaction was observed between aflatoxin & salinomycin on any of the parameters measured.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

这项研究旨在探讨盐霉素联合长春新碱对Jurkat细胞增殖和凋亡的影响及其可能机制。通过CKK-8实验检测Jurkat细胞的增殖，使用流式细胞术来评估细胞凋亡。通过Western blot测量BCL-2、caspase-3和caspase-8的水平。结果显示，无论是单独使用还是联合使用，盐霉素或长春新碱均以剂量依赖性方式抑制Jurkat细胞的增殖。盐霉素联合长春新碱对细胞增殖的抑制作用比单独使用任一化合物更为明显（P<0.05）。Western blot分析显示，盐霉素和长春新碱联合使用显著降低了BCL-2蛋白的表达，并显著增加了caspase 3和caspase 8蛋白的表达。此外，盐霉素和长春新碱联合使用协同促进了Jurkat细胞的凋亡（P<0.05）。盐霉素和长春新碱联合使用协同抑制了T细胞急性淋巴细胞性白血病Jurkat细胞的增殖并促进了其凋亡。

This study was aimed to investigate the effect of salinomycin combined with vincristine on the proliferation and apoptosis of Jurkat cells and its possible mechanisms. The proliferation of Jurkat cells was examined by CKK-8 assay. Flow cytometry was used to assess cellular apoptosis. Levels of BCL-2, caspase-3, and caspase- 8 were measured by Western blot. The salinomycin or vincristine, either alone or in combination, inhibited the proliferation of Jurkat cells in a dose-dependent manner. Salinomycin combined with vincristine produced more obvious inhibition of cell proliferation than either compound used alone (P<0.05). Western blot analysis showed that the combined use of Sal and VCR reduced the expression of BCL-2 protein, and increased expression of caspase 3 and caspase 8 protein, more significantly. Furthermore, combination of Sal and VCR synergistally promoted apoptosis of the Jurkat cells (P<0.05). The combination of salinomycin and vincristine synergistically inhibits proliferation and promotes apoptosis of T-cell acute lymphoblastic leukemia Jurkat cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：盐霉素是一种兽药，用于预防肉鸡、烤鸡和后备鸡由艾美耳球虫属的Eimeria tenella、E. necatrix、E. acervulina、E. maxima、E. bruneTTi和E. mivati引起的球虫病。它还用于预防由Eimeria disperSA和E. leTTyae引起的鹌鹑球虫病。人类暴露和毒性：研究了盐霉素对人类非恶性细胞的细胞毒性和遗传毒性。使用来自10个人的原代人鼻粘膜细胞（单层和小型器官培养）和外围血淋巴细胞来研究盐霉素（0.1-175 uM）的细胞毒性，通过annexin-propidiumiodide-和M