(2R)-2-[(2R,5S,6R)-6-[(1S,2S,3S,5R)-5-[(3S,5R,7S,9S,10S,12R,15R)-3-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyl-tetrahydropyran-2-yl]-15-hydroxy-3,10,12-trimethyl-4,6,8-trioxadispiro[4.1.5^{7}.3^{5}]pentadec-13-en-9-yl]-2-hydroxy-1,3-dimethyl-4-oxo-heptyl]-5-methyl-tetrahydropyran-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: (2R)-2-[(2R,5S,6R)-6-[(1S,2S,3S,5R)-5-[(3S,5R,7S,9S,10S,12R,15R)-3-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyl-tetrahydropyran-2-yl]-15-hydroxy-3,10,12-trimethyl-4,6,8-trioxadispiro[4.1.5^{7}.3^{5}]pentadec-13-en-9-yl]-2-hydroxy-1,3-dimethyl-4-oxo-heptyl]-5-methyl-tetrahydropyran-2-yl]butanoic acid
• 英文别名: (2R)-2-[(2R,5S,6R)-6-[(2S,3S,4S,6R)-6-[(3S,5R,7S,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-WCORQMKCSA-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；这重新聚焦了它对治疗人类癌症的重要性。在本研究中，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，具有高内在清除率。SAL的代谢主要是由CYP酶介导的；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是主要负责代谢SAL的主要酶，因此在大鼠中进行了体内药代动力学研究，以检查酮康唑（KTC）的伴随给药对SAL药代动力学的影响。KTC作为一种选择性的CYP3A4抑制剂，在伴随KTC给药的大鼠中，显著增加了SAL的系统暴露，AUC0-a增加了7倍，SAL的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

• 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基因毒性影响。使用来自10个人的原代人类鼻粘膜细胞（单层和小型器官培养）和外周血淋巴细胞来研究盐霉素（0.1-175 uM）的细胞毒性影响，通过annexin-碘化丙啶-和MTT测试。使用彗星实验评估DNA损伤。此外，通过ELISA分析白细胞介素-8的分泌。流式细胞仪和MTT检测显示，在10-20 uM的低盐霉素浓度下，鼻粘膜细胞和淋巴细胞具有显著的细胞毒性作用。没有观察到基因毒性效应。在5 uM时，IL-8分泌增加。在抗肿瘤治疗的浓度下观察到了盐霉素引起的细胞毒性和促炎效应。动物研究：有报道称，当盐霉素意外喂给各种动物时，会导致致命的后果。在一个饲养600只48周龄种火鸡的五个火鸡繁殖场的其中一个房屋中，突然爆发了死亡事件，怀疑与饲料有关。火鸡喘息并变得卧倒；受影响的火鸡中有21.7%死亡。组织学病变仅限于骨骼肌，包括变性和坏死，被认为是与离子载体中毒相容的。从受影响的房屋中取出的饲料样本分析显示，每吨饲料中含有13.4至18.4克的盐霉素。为了进一步研究盐霉素对火鸡的影响，进行了五次为期7天的试验，分别使用336、24、24、40和40只7、11、15、27和32周龄的雄性火鸡。随着火鸡年龄的增长，盐霉素的毒性增加。当7周龄的火鸡被喂食含有44或66 ppm盐霉素的饲料时，84只中只有1只死亡；当27或32周龄的火鸡被喂食这些量时，20只中有13只死亡。22 ppm的盐霉素在幼年时期倾向于抑制生长速度，在老年时期防止或减少生长并增加死亡率。还有报道称，六匹马因误食盐霉素而中毒。症状的范围，包括厌食、腹痛、虚弱和共济失调，与那些因相关离子载体蒙奈森中毒的马的描述相似。在另一次中毒事件中，马被喂食了制造商错误准备的含有61 mg/kg盐霉素的浓缩物。所有马都出现了严重的临床中毒症状。尽管进行了治疗，但八匹马在三到六天内死亡。另外十匹马倒下并不得不被安乐死。只有六匹马幸存。实验室结果的主要特点是酶水平极高和碱中毒。最典型的临床变化是后肢瘫痪。还报道了一群猫因摄入了含有盐霉素的干猫粮而引发的中毒性多发性神经病。从823只猫中收集了流行病学和临床数据，约占风险猫的1%。在21只受影响的猫中进行了尸检。受影响的猫突然出现跛行和后肢瘫痪，然后是前肢。临床和病理检查表明是一种涉及感觉和运动神经的远端多发性神经病。在牛群中发生的一起因长期摄入有毒水平的盐霉素而导致的毒性爆发事件中，也报告了临床体征和病理变化。380头牛中有39头出现了与心力衰竭一致的体征，其中8头死亡。临床体征包括呼吸困难、呼吸急促、心动过速和运动不耐受。对两头牛进行了尸检，其中一头牛有提示充血性心力衰竭的宏观病变，即肺水肿、胸腔积液和肝肿大。组织病理学显示，主要表现为广泛的心肌纤维萎缩，多灶性肥大和间质和替代性纤维化。肝脏和肺部的病变与充血性心力衰竭一致。最后，据报道，一群羊在喂食含有盐霉素的饲料后，死亡率达到了100%。在喂食后的第二天早上，发现了78只死羊，其中一只出现了惊厥发作。尸检显示肺充血和水肿，胃中有出血，肾脏苍白且心肌中有白色条纹。

IDENTIFICATION AND USE: Salinomycin is a veterinary drug used for the prevention of coccidiosis in broiler, roaster and replacement chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati. It is also used for the prevention of coccidiosis in quail caused by Eimeria dispersa and E. lettyae. HUMAN EXPOSURE AND TOXICITY: The cytotoxic and genotoxic effects of salinomycin were investigated in human non-malignant cells. Primary human nasal mucosa cells (monolayer and mini organ cultures) and peripheral blood lymphocytes from 10 individuals were used to study the cytotoxic effects of salinomycin (0.1-175 uM) by annexin-propidiumiodide- and MTT-test. The comet assay was performed to evaluate DNA damage. Additionally, the secretion of interleukin-8 was analyzed by ELISA. Flow cytometry and MTT assay revealed significant cytotoxic effects in nasal mucosa cells and lymphocytes at low salinomycin concentrations of 10-20 uM. No genotoxic effects could be observed. IL-8 secretion was elevated at 5 uM. Salinomycin-induced cytotoxic and pro-inflammatory effects were seen at concentrations relevant for anti-cancer treatment. ANIMAL STUDIES: There are numerous reports of fatal outcomes when salinomycin is accidently fed to various animals. A sudden outbreak of mortality in one house of 600 48-week-old male breeder turkeys on a five-house turkey breeder farm was suspected to be feed-related. The turkeys gasped and became recumbent; 21.7% of affected turkeys died. Histological lesions, limited to skeletal muscle, consisted of degeneration and necrosis and were judged compatible with ionophore toxicosis. Feed samples from the affected house were analyzed and shown to contain 13.4 to 18.4 g of salinomycin per ton of feed. To further study the effects of salinomycin on turkeys, five 7-day trials using 336, 24, 24, 40, and 40 male turkeys when 7, 11, 15, 27, and 32 weeks of age, respectively. Salinomycin became more toxic as the age of the turkeys increased. When 7-week-old turkeys were fed diets containing 44 or 66 ppm salinomycin, only 1 of 84 died; when turkeys 27 or 32 weeks of age were fed those amounts, 13 of 20 died. Salinomycin at 22 ppm tended to depress rate of growth at young ages and to prevent or decrease growth and to increase mortality at older ages. Accidental poisonings were also reported in six horses fed salinomycin. The range of signs, including anorexia, colic, weakness and ataxia bore similarities to those described in horses poisoned with the related ionophore monensin. In another poisoning, horses were fed a concentrate containing 61 mg/kg salinomycin as faulty prepared by the manufacturer. All horses developed severe clinical signs of intoxication. Despite therapy eight horses died within three to six days. Ten others became recumbent and had to be euthanized. Only six horses survived. The dominating laboratory results were very high enzyme levels and alkalosis. The most characteristic clinical change appeared as paralysis of the hindlimbs. An outbreak of toxic polyneuropathy in cats that had ingested dry cat food contaminated with salinomycin has also been reported. Epidemiologic and clinical data were collected from 823 cats, or about 1% of the cats at risk. In 21 affected cats, postmortem examination was performed. The affected cats had acute onset of lameness and paralysis of the hindlimbs followed by the forelimbs. Clinical and pathologic examination indicated a distal polyneuropathy involving both the sensory and motor nerves. The clinical signs and pathology in an outbreak of toxicity in feedlot cattle attributed to the ingestion of toxic levels of salinomycin over an extended period of 11 weeks have also been reported. Thirty-nine out of 380 cattle developed signs consistent with cardiac failure and 8 of these died. Clinical signs included dyspnea, tachypnea, tachycardia, and exercise intolerance. Two cattle were necropsied and in one there were macroscopic lesions suggestive of congestive heart failure, namely pulmonary edema, hydrothorax and hepatomegaly. Histopathology revealed a chronic cardiomyopathy characterized principally by extensive myocardial fiber atrophy with multifocal hypertrophy and interstitial and replacement fibrosis. Hepatic and pulmonary lesions were consistent with those of congestive cardiac failure. Finally, 100% mortality was reported in a herd of sheep that were given feed containing salinomycin. The morning after the feeding, 78 sheep were found dead and one of them showed convulsive seizures. Postmortem examination revealed pulmonary congestion and edema, hemorrhages in abomasum, large pale kidney and white streak lines in myocardium.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用