竹桃霉素 | 3922-90-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 竹桃霉素
• 英文名称: oleandomycin
• 英文别名: (3R,5S,6S,7R,8S,9R,12R,13R,14S,15R)-6-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-hydroxy-8-[(2R,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-5,7,9,12,13,15-hexamethyl-1,11-dioxaspiro[2.13]hexadecane-10,16-dione
• CAS: 3922-90-5
• 化学式: C₃₅H₆₁NO₁₂
• 分子量: 687.869
• InChiKey: RZPAKFUAFGMUPI-QESOVKLGSA-N

物化性质

• 熔点：
  110 °C (decomp)
• 沸点：
  802.6±65.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 颜色/状态：
  White, amorphous powder
• 蒸汽压力：
  3.4X10-25 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 8.84 (tertiary amine)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  48
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  166
• 氢给体数：
  3
• 氢受体数：
  13

ADMET

代谢

大环内酯类药物的代谢失活通常是广泛的，但相对比例取决于给药途径和特定的抗生素。

Metabolic inactivation of the macrolides is usually extensive, but the relative proportion depends on the route of administration and th particular antibiotic. ... /Macrolides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

大环内酯类抗生素可能不应与氯霉素或林可酰胺类药物一起使用，因为它们可能会竞争相同的50S核糖体结合位点，尽管这种潜在相互作用的体内意义尚不清楚。大环内酯类药物在酸性环境中的活性会受到抑制。用于静脉注射的大环内酯类药物制剂与许多其他药物制剂不相容。... /大环内酯类/

Macrolide antibiotics probably should not be used with chloramphenicol or the lincosamides because they may compete for the same 50 S ribosomal binding site, although the in vivo significance of this potential interaction is unclear. Activity of macrolides is depressed in acidic environments. Macrolide preparations for parenteral administration are incompatible with many other pharmaceutical preparations. ... /Macrolides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

... /能够/ 诱导狗的III期移行肌电复合活动（MMC）并增加平滑肌的收缩力 ... 这种特性在一定程度上被一些大环内酯类抗生素共享，包括奥莱andomycin ... /胃动素：大环内酯类和红霉素/

... /The ability to/ Induce phase III migrating myoelectric complex (MMC) activity in dogs and increase smooth muscle contractility ... is shared to varying extents by some macrolide antibiotics, including oleandomycin ... /Motilin: macrolides and erythromycin/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

四环素（TC）和奥利万星（OM）对急性感染小鼠四种金黄色葡萄球菌（包括对TC或OM耐药的菌株）的联合作用通过定量测定单一药物和联合药物的防护效力进行了研究。协同作用的程度通过协同比率（SR）来表示，即实验确定的联合药物效力与假设的两种药物叠加效果效力之比。在4种金黄色葡萄球菌中的3种，通过测定50%有效剂量和对SR进行统计分析，证明了TC和OM或三乙酰奥利万星（TAO）之间的协同作用。这些药物对感染的菌株的协同防护程度不同，且不依赖于对抗生素的敏感性或在体外的协同作用程度。在给小鼠联合使用TC和OM时，没有观察到急性毒性作用的协同增强。

The combination effect of tetracycline (TC) and oleandomycin (OM) on acute infection of mice with four strains of Staphylococcus aureus including TC or OM resistant ones was examined by the quantitative determination of protective potencies of single and combined drugs. The grade of synergism was expressed by the synergistic ratio (SR), a ratio of experimentally determined potency of the combined drug over a hypothetical potency in which additive effect of the both drugs is assumed. With 3 out of the 4 strains of S. aureus synergism between TC and OM or triacetyloleandomycin (TAO) was demonstrated by the determination of the 50% effective dose and by statistical examination of the SR. The grade of synergistic protection by these drugs varied with the strains infected and it did not depend upon the sensitivity to antibiotics or grade of synergism in vitro. There was no synergistic enhancement of acute toxic action in the combined administration of TC and OM to mice.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。密切观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的灭菌敷料覆盖皮肤烧伤……。/毒物A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用带气囊的面罩进行正压通气技术可能有益。考虑使用药物治疗肺水肿...。对于严重的支气管痉挛，可以考虑给予β激动剂，如沙丁胺醇...。监测心率和必要时治疗心律失常...。开始静脉输注5%葡萄糖水（D5W）/SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象...。使用地西泮或劳拉西泮治疗癫痫...。使用丙美卡因氢氯化物协助眼部冲洗...。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大环内酯类药物在组织中广泛分布，其浓度与血浆中相似，有时甚至更高。它们实际上会在许多细胞内积累，包括巨噬细胞，在这些细胞中的浓度可能是血浆浓度的20倍或更高。这种积累部分解释了一些大环内酯类药物（例如，蒂尔米科辛）的特征性长给药间隔。大环内酯类药物倾向于在脾脏、肝脏、肾脏特别是肺中浓缩。它们进入胸膜和腹水，但不会进入脑脊液（除非脑膜发炎，否则仅为血浆浓度的2-13%）。它们在胆汁和乳汁中浓缩。多达75%的剂量与血浆蛋白结合，并且它们与酸性α1-糖蛋白结合，而不是与白蛋白结合。/大环内酯类药物/

Macrolides become widely distributed in tissues, and concentrations are about the same as in plasma, or even higher in some instances. They actually accumulate within many cells, including macrophages, in which they may be > or = 20 times the plasma concentration. This accumulation accounts in part for the long dosing interval that characterizes some macrolides (eg, tilmicosin). ... Macrolides tend to concentrate in the spleen, liver, kidneys, and particularly the lungs. They enter pleural and ascitic fluids but not the CSF (only 2-13% of plasma concentration unless the meninges are inflamed). They concentrate in the bile and milk. Up to 75% of the dose is bound to plasma proteins, and they bind to alpha1-acid glycoproteins rather than to albumin. /Macrolides/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大环内酯类药物如果未被胃酸灭活，则可从胃肠道被很好地吸收。在大多数情况下，血浆药物浓度在1-2小时内达到峰值，但由于食物的存在，吸收模式可能不稳定，且可能取决于所使用的盐或酯。从瘤胃网胃的吸收通常会有延迟，且不可靠。/大环内酯类药物/

Macrolides are readily absorbed from the GI tract if not inactivated by gastric acid. ... Plasma levels peak within 1-2 hours in most cases, although absorption patterns may be erratic due to the presence of food and may depend on the salt or ester used. Absorption from the ruminoreticulum is usualy delayed and is unreliable. /Macrolides/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大环内酯类抗生素及其代谢物主要通过胆汁排泄（大于60%），并常经历肠肝循环。尿液清除可能较慢且多变（通常小于10%），但在静脉给药后可能成为更重要的消除途径。大环内酯类药物在乳汁中的浓度通常比血浆中的浓度高几倍，尤其是在乳腺炎时。

Macrolide antibiotics and their metabolites are excreted mainly in the bile (> 60%) and often undergo enterohepatic cycling. Urinary clearance may be slow and variable (often <10%) but my represent a more significant route of elimination after parenteral administration. The concentration of macrolides in milk often is several times greater than in plasma, especially in mastitis. /Macrolide/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

奥莱andomycin（OLD）的药代动力学研究包括静脉和口服给药，单独给药以及肌肉注射美他modulesole或地塞米松预处理后的给药，在健康狗中进行研究。单独静脉注射奥莱andomycin（10 mg/kg作为一次性注射）后，消除半衰期（t 1/2 beta）、分布体积（Vd, area）、体清除率（ClB）和浓度-时间曲线下面积（AUC）分别为1.60小时、1.11 L/kg、7.36 (ml/kg)/分钟和21.66 ug hr/ml。美他modulesole或地塞米松预处理后没有统计学上的显著差异。单独口服给药奥莱andomycin后，t 1/2 beta、最大血浆浓度（Cmax）、Cmax时间（tmax）、平均吸收时间和绝对生物利用度（Fabs）分别为1.6小时、5.34 ug/ml、1.5小时、1.34小时和84.29%。美他modulesole预处理显著降低了Cmax值（2.93 ug/ml），但平均吸收时间值（2.23小时）显著增加。口服给药奥莱andomycin后，地塞米松预处理也导致药代动力学参数的统计学显著变化。Cmax增加（8.24 ug/ml），tmax（0.5小时）和平均吸收时间（0.45小时）降低。

The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of oleandomycin alone (10 mg/kg as bolus), the elimination half-life (t 1/2 beta, volume of distribution (Vd, area), body clearance (ClB) and area under the concentration time curve (AUC) were 1.60 hr, 1.11 L/kg. 7.36 (ml/kg)/min and 21.66 ug hr/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of oleandomycin alone, the t 1/2 beta, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean absorption time and absolute bioavailability (Fabs) were 1.6 hr, 5.34 ug/ml, 1.5 hr, 1.34 hr and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for Cmax (2.93 ug/ml) but the mean absorption time value (2.23 hr) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of oleandomycin following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 ug/ml) and the tmax (0.5 hr) and mean absorption time (0.45 hr) were lower.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大动物种中对大环内酯类药物的分布了解不足，无法预测人类中大环内酯类药物的药代动力学。为了更好地理解不同物种中大环内酯类抗生素药代动力学的差异，研究了红霉素、奥莱霉素和泰乐菌素在几种哺乳动物物种中的分布。通常，这些药物在静脉给药后的血清浓度-时间曲线可以用双室动力学模型描述，并且在同一物种内相似。这些药物被迅速清除，导致终末半衰期小于2小时。比较它们的药代动力学发现，与同一物种内的差异相比，抗生素分布在不同动物物种间的变化更大。当药代动力学数据被拟合到一种异速生长模型时，分布容积、清除率和半衰期的对数与体重的对数呈线性关系。根据这些关系，外推了红霉素和奥莱霉素的人体药代动力学，并发现其近似于观察到的人体药代动力学。

Knowledge of the disposition of macrolides in a single animal species has been insufficient for the prediction of the pharmacokinetics of macrolides in humans. To better understand the species differences in the pharmacokinetics of macrolide antibiotics, the disposition of erythromycin, oleandomycin, and tylosin in several mammalian species was examined. Generally, the serum concentration versus time profiles of these drugs after intravenous administration were described by two-compartment kinetic models and were similar within each species. These drugs were rapidly cleared, resulting in terminal half-lives of less than 2 h. Comparison of their pharmacokinetics showed greater variation in antibiotic disposition among animal species than noted for the differences within a species. When the pharmacokinetic data was fitted to an allometric model, the logarithms of volume of distribution, clearance, and half-life were linearly related to the logarithms of body weight. From these relationships, the human pharmacokinetics of erythromycin and oleandomycin were extrapolated and found to approximate observed human pharmacokinetics.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

生物活性方面，Oleandomycin 是一种大环内酯类抗生素，其结构与红霉素相近，因此抗菌谱也类似。

反应信息

• 作为反应物：
  描述：

  竹桃霉素 在 chromium dichloride 、 盐酸 作用下， 以 丙酮 为溶剂， 反应 12.0h， 以92%的产率得到8-methylene-oleandomycin
  参考文献：
  名称：

  由夹竹桃霉素衍生的聚酮内酯对映选择性合成大环内酯

  摘要：

  聚酮内酯，8-甲基-3,5,11-trioxo-oleandolide，它是从夹竹桃的新苷元通过四氧化钌氧化得到的，在溴化镁存在下被硼氢化锌立体选择性还原得到大环内酯，（ 5R,8R,9R)-9-dihydro-8-methyl-epi-oleandolide，收率良好。

  DOI：

  10.1246/cl.1987.187
• 作为产物：
  描述：

  (1S,2R,2'R,5R,6R,7R,8R,9R,12S,13S,17R)-15-(4-bromophenyl)-7,9-dihydroxy-2,5,6,8,12,17-hexamethyl-4,14,16-trioxaspiro[bicyclo[11.3.1]heptadecane-10,2'-oxiran]-3-one 在 palladium hydroxide - carbon 重铬酸吡啶 、 氢气 、 silver trifluoromethanesulfonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 甲苯 为溶剂， 反应 14.0h， 生成 竹桃霉素
  参考文献：
  名称：

  通过完整的糖苷配基油酸内酯合成油酸霉素

  摘要：

  通过将两个糖单元引入完整的糖苷配基油酸内酯中，重新构建了奥林霉素，该糖苷酸首先通过8-外-亚甲基衍生物的立体选择性氧化合成。

  DOI：

  10.1016/s0040-4039(00)80397-4

文献信息

• [EN] PHOSPHODIESTERASE INHIBITORS<br/>[FR] INHIBITEURS DE PHOSPHODIESTÉRASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2009089027A1

  公开（公告）日：2009-07-16

  The invention relates to compounds of formula I useful for inhibiting phosphodiesterase-4.

  这项发明涉及到公式I的化合物，用于抑制磷酸二酯酶-4。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [EN] ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2019199979A1

  公开（公告）日：2019-10-17

  The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.

  本申请提供了以下化合物的公式：还提供了使用这些化合物杀灭细菌生长和治疗细菌感染的方法。