抗霉素A1 | 1397-94-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 抗霉素A1
• 中文别名: 二氫沙米汀；抗黴素A1；2-庚基-4-羟基喹啉-1-氧化物
• 英文名称: antimycin A1
• 英文别名: antimycin A₁；Antimycine A；antimycin A；antimycin-a；antimyin a；antimycin；[3-[(3-formamido-2-hydroxybenzoyl)amino]-8-hexyl-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl] 3-methylbutanoate
• CAS: 1397-94-0；642-15-9
• 化学式: C₂₈H₄₀N₂O₉
• 分子量: 548.634
• InChiKey: UIFFUZWRFRDZJC-UHFFFAOYSA-N

物化性质

• 熔点：
  149.5℃
• 比旋光度：
  D26 +76° (c = 1 in chloroform)
• 沸点：
  620.81°C (rough estimate)
• 密度：
  1.2468 (rough estimate)
• 溶解度：
  DMF：可溶； DMSO：可溶；乙醇：可溶；甲醇：可溶
• 物理描述：
  Antimycin a is a solid. Specific uses for Antimycin A were not found. Antimycin A1,and Antimycin A3 are reported as antibiotics produced by Streptomyces for use as a fungicide and possibly as an insecticide and miticide. Registered only as a pesticide in the U.S. (EPA, 1998)
• 颜色/状态：
  Crystals
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  157
• 氢给体数：
  3
• 氢受体数：
  9

ADMET

毒理性

• 相互作用

Antimycin A在消除氧气消耗的浓度下，对t-丁基过氧化氢在U937细胞中引发的毒性有轻微的抑制作用，尽管这种作用在统计学上是显著的。保护作用在处理后6小时观察到，但在24小时后不再明显。出人意料的是，这些事件与由低浓度t-丁基过氧化氢产生的DNA单链断裂的显著积累有关。在t-丁基过氧化氢处理过程中发现产生了以氧和碳为中心的自由基，而抗霉素A显著降低了它们的形成。因此，抑制复合物III水平的电子传递似乎（a）减少了介导t-丁基过氧化氢引起的至少部分致命效果的毒性物种的形成，并（b）促进了在低浓度t-丁基过氧化氢下生成的DNA损伤物种的形成。Rotenone和氰化物分别抑制复合物I和IV，它们并未影响t-丁基过氧化氢引发的DNA损伤。这些结果表明，DNA单链断裂并未介导t-丁基过氧化氢的毒性，特定的线粒体功能可能调节有机过氧化物产生的毒性和DNA损伤物种的形成。

Antimycin A at levels that abolish oxygen consumption had a slight, although statistically significant, inhibitory effect on the toxicity elicited by t-butylhydroperoxide in U937 cells. The protective effect was observed after 6 hr of post-treatment incubation, but was no longer apparent after 24 hr. Unexpectedly, these events were associated with a marked accumulation of DNA single-strand breaks produced by low levels of t-butylhydroperoxide. Both an oxygen- and a carbon-centred radical were found to arise during treatment with t-butylhydroperoxide, and their formation was significantly lowered by antimycin A. Thus inhibition of electron transport at the level of complex III appears (a) to decrease the formation of toxic species which mediate, at least partially, the lethal effects elicited by t-butylhydroperoxide, and (b) to enhance the formation of DNA-damaging species generated at low concentrations of t-butylhydroperoxide. Rotenone and cyanide, which respectively inhibit complexes I and IV, did not affect DNA damage elicited by t-butylhydroperoxide. These results suggest that DNA single-strand breaks do not mediate the toxicity of t-butylhydroperoxide, and that specific mitochondrial functions might modulate the formation of the toxic and of DNA-damaging species generated by organic hydroperoxides.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，并在需要时辅助通气。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，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于昏迷、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽插管以控制气道。使用带有气囊面罩的装置进行正压通气技术可能有益。监测心率和必要时治疗心律失常。 ... 开始静脉输液，使用5%葡萄糖盐水/生理盐水： "保持开放"，最低流速/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。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（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。 /毒药A和B/

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

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/替代体外测试/研究了代谢毒素抗霉素A（4.1微克/毫升）和2-脱氧葡萄糖（32.2毫摩尔）对洗涤后人血小板中血清素（5HT）的摄取和囊泡储存的影响。在添加代谢毒素后15秒内，H3-5HT开始从囊泡移动到细胞质中。在毒素添加后30分钟，几乎所有血小板的5HT似乎都存在于细胞质中。代谢毒素迅速作用，在添加后1分钟内，将细胞外介质中的H3-5HT的质膜摄取量减少了大约20%。这可能是直接影响，而不是由于细胞质或囊泡中5HT的改变，因为即使在囊泡储存位点数量减少到正常数量的<10%的情况下，添加代谢毒素后也出现了类似的减少。

/ALTERNATIVE IN VITRO TESTS/ The effects of the metabolic poisons antimycin A (4.1 mug/mL) and 2-deoxyglucose (32.2 mM) on the uptake and vesicular storage of serotonin (5HT) in washed human platelets were examined. Within 15 s after the addition of the metabolic poisons, H3-5HT began to move from vesicles into the cytoplasm. By 30 min after poison addition, essentially all the platelet 5HT appeared to be cytoplasmic. The metabolic poisons acted rapidly to decrease plasma-membrane uptake of H3-5HT from the extracellular medium by approximately 20% within 1 min after their addition. This may represent a direct effect rather than one resulting from altered cytoplasmic or vesicular 5HT, since platelets with < 10% of the normal number of vesicular storage sites exhibited a similar reduction after addition of the metabolic poisons.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

体外替代测试/研究了鱼藤酮、抗霉素A、氰化钾和2,4-二硝基苯酚对健康男性精液样本中精子运动能力的影响。在所使用的浓度下（10-6至10-3），这些化合物均未抑制精子运动。

/ALTERNATIVE IN VITRO TESTS/ The effects of rotenone, antimycin A, potassium cyanide and 2,4-dinitrophenol, on human sperm motility, were studied using semen samples from healthy men. None of the /compounds/ inhibited sperm motility at concentrations used (10-6 to 10-3).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)

制备方法与用途

生物活性

Antimycin A1 是泛醇-细胞色素 c 氧化还原酶的特定电子传递抑制剂。它通过抑制 HIF-1α 激活导致的 VEGF 产生减少来抑制血管生成。

体外研究

Antimycin A，由 Streptomyces 种类产生的一种抗生素，是一种抗菌素，还具有抗真菌、杀虫、驱线虫及杀鱼特性。它能抑制 Bcl-2 和 Bcl-xL 蛋白质，诱导细胞凋亡。

化学性质

Antimycin A1 为白色结晶体，不溶于水但易溶于乙醇，并且极易溶解在丙酮和氯仿中。其熔点分别为：A1 约为 149-150℃；A3 约为 170-171.5℃。A1 在乙醇中的最大吸收波长为226nm 和 320nm，而 A3 在甲醇中的最大吸收波长是225nm 和 320nm。A1 的比旋光度在氯仿中为 [α]26D +76° (1%，氯仿)，A3 为+64.3°(氯仿)。其毒性较低，大鼠经口 LD50 值为 1469mg/kg（A1）。

用途

Antimycin A1 是琥珀酸氧化酶的抑制剂和生物色素系统的电子传递阻断剂，同时也可以作为细胞呼吸抑制剂，并具有抗病毒及抗真菌作用。

生产方法

通过培养链霉菌并经醇提、浓缩制备复合物粗晶体，再利用甲醇：水：四氯化碳：己烷的逆流分配分离技术获得纯品。

文献信息

• [EN] PHENYLPYRIDYLPYRIDONES FOR USE AS ANTIMALARIAL AGENTS<br/>[FR] PHÉNYLPYRIDYLPYRIDONES DESTINÉES À ÊTRE UTILISÉES COMME AGENTS ANTIPALUDÉENS
  申请人：GLAXO GROUP LTD

  公开号：WO2010142741A1

  公开（公告）日：2010-12-16

  4-Pyridone derivatives of Formula (I) wherein R1, R2, X and n are as defined in the description and pharmaceutically acceptable salts thereof, pharmaceutical formulations thereof and their use in chemotherapy of certain parasitic infections such as malaria, are provided.

  提供公式（I）中R1、R2、X和n的4-吡啶酮衍生物，其中R1、R2、X和n的定义如描述中所述，并其药用盐，制剂以及在化疗特定寄生虫感染（如疟疾）中的应用。
• COMPOSITIONS FOR THE PREVENTION OF HEARING LOSS
  申请人：Ting Therapeutics LLC

  公开号：EP3310783B1

  公开（公告）日：2020-11-04
• COMPOUNDS AND THERAPEUTIC USES
  申请人：Unity Biotechnology, Inc.

  公开号：US20170281649A1

  公开（公告）日：2017-10-05

  Disclosed herein are compounds that are effective for treatment of various disease states associated with senescence. The disclosed compounds can be used to eliminate senescent cells for disease treatment. The dosing of the compounds includes both single administration and regimens of cycling dosages.