Kasugamycin | 11030-24-3

• 物质功能分类: 原料药 - 抗生素类药物 - 农用抗生素
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: Kasugamycin
• 英文别名: 2-amino-2-[(2R,3S,5S,6R)-5-amino-2-methyl-6-[(2S,3S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxyoxan-3-yl]iminoacetic acid
• CAS: 11030-24-3；6980-18-3
• 化学式: C₁₄H₂₅N₃O₉
• 分子量: 379.36
• InChiKey: PVTHJAPFENJVNC-UQTMRZPGSA-N

物化性质

• 沸点：
  507.24°C (rough estimate)
• 密度：
  1.2554 (rough estimate)
• 溶解度：
  可溶于水基（轻微），水（轻微）
• 熔点：
  203 °C (dec)
• 蒸汽压力：
  <1.3X10-4 mm Hg at 25 °C
• 分解：
  When heated to decomposition it emits toxic vapors of /nitrogen oxides/.
• 解离常数：
  pKa1 = 3.23 /carboxylic acid/; pKa2 = 7.73 /cyclic primary amine/; pKa3 = 11.0 /secondary amine/

计算性质

• 辛醇/水分配系数(LogP)：
  -6.7
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  221
• 氢给体数：
  8
• 氢受体数：
  11

ADMET

代谢

在番茄代谢研究中，番茄果实和叶子的代谢物轮廓相似。... 植物中春日霉素的主要代谢途径涉及母化合物的共轭，转化为春日霉素酸，随后是春日霉素酸的共轭。认为春日霉素转化为2-N-乙酰春日霉素和春日诺比奥斯胺是一条次要的代谢途径。母化合物（即春日霉素本身）是所有收获间隔期所有样本中主要识别的成分。

In the tomato metabolism study, the metabolite profile was similar for tomato fruit and foliage. ... The major metabolic pathway of kasugamycin in plants involves conjugation of the parent compound, conversion to kasugamycinic acid, and subsequent conjugation of kasugamycinic acid. Conversion of kasugamycin to 2-N-acetyl kasugamycin and kasuganobiosamine was thought to be a minor metabolic route. Parent compound (kasugamycin per se) was the major identified component in all samples from all harvest intervals.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠代谢研究中，暴露后168小时的平均放射性回收率范围从91%到97%，大部分剂量在48小时内通过粪便（81.9-93.9%）和尿液（1.26-3.07%）回收。... 大鼠对春日霉素的吸收和代谢有限（小于剂量的5%），且不受性别、剂量水平或给药持续时间的 影响。母体化合物是在尿液、粪便、肝脏、肾脏和血浆中鉴定出的主要成分。少量（小于剂量的1%）的代谢物春日诺比胺在尿液、肝脏、肾脏和血浆中被鉴定出，但在粪便中没有检测到。

In the rat metabolism study, the mean radioactivity recovery 168 hours after exposure ranged from 91 to 97%, with the majority of the dose recovered within 48 hours in the feces (81.9-93.9%) and urine (1.26-3.07%). ... The absorption and metabolism of kasugamycin in rats was limited (less than 5% of the dose) and was not affected by sex, dose level, or duration of dosing. The parent compound was the major component identified in the urine, feces, liver, kidney, and plasma. Minor amounts (less than 1% of the dose) of the metabolite kasuganobiosamine were identified in urine, liver, kidney, and plasma, but none was detected in the feces.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

神经毒素 - 其他中枢神经系统神经毒素

Neurotoxin - Other CNS neurotoxin

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 毒性数据

LC50 (大鼠) > 2,400 毫克/立方米/4小时

LC50 (rat) > 2,400 mg/m3/4h

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 解毒与急救

基本治疗：建立专利气道（如需要，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，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……。预防癫痫发作，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0.9%的生理盐水（NS）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，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

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

高级治疗：对于昏迷的患者、严重肺水肿的患者或严重呼吸窘迫的患者，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。考虑对肺水肿进行药物治疗...。对于严重的支气管痉挛，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D5W/SRP：“保持开放”，最小流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液。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/

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)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/以2000毫克/千克的剂量通过静脉注射、皮下注射或腹腔注射卡苏霉素给小鼠，既没有观察到效果也没有导致死亡。[Krieger, R. (ed.).农药毒理学手册。第1卷，第2版。2001年。学术出版社，加利福尼亚州圣地亚哥，第147页]

/LABORATORY ANIMALS: Acute Exposure/ Doses of 2000 mg/kg kasugamycin, admin iv, sc, or ip to mice, caused neither observable effects nor death.[Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 147]

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当一只兔子静脉注射了...每千克体重100毫克的春日霉素后，这种杀菌剂在8小时内从血液中消失，注射物质的96%在注射后8小时内通过尿液排出；春日霉素在尿液中的浓度在45分钟后最高，达到43毫克/毫升。

When a rabbit was sc injected with ... /100 mg/kg/ of kasugamycin, the fungicide disappeared from the blood within 8 hr, and 96% of the injected material was excreted into urine in 8 hr after injection; kasugamycin concn in the urine was highest (43 mg/mL) after 45 min.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给小鼠每千克100毫克的春日霉素表明药物被迅速吸收，并在6小时内通过尿液排出了43%到68%。

Oral admin of 100 mg/kg kasugamycin to mice indicated rapid absorption and 43 to 68% excretion with urine in 6 hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给人体静脉注射1.0克春日霉素后，大约63%的杀菌剂在8小时内以未改变的形式随尿液排出。

On im injection of 1.0g kasugamycin into humans, about 63% of the fungicide was excreted unchanged with urine in 8 hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠代谢研究中，暴露168小时后的平均放射性回收率范围在91%到97%，大部分剂量在48小时内通过粪便（81.9-93.9%）和尿液（1.26-3.07%）回收。在单次低剂量或高剂量给药后约一小时，在男女大鼠的血浆中发现了最高浓度。在单次低剂量或高剂量给药后一到六小时内，肾脏、膀胱和淋巴结中积累的春日霉素比血液中多，但在168小时后，这些组织中几乎没有发现春日霉素。大鼠对春日霉素的吸收和代谢有限（剂量小于5%），且不受性别、剂量水平或给药持续时间的影响。原化合物是在尿液、粪便、肝脏、肾脏和血浆中鉴定出的主要成分。少量（小于剂量的1%）代谢物春日诺比胺在尿液、肝脏、肾脏和血浆中被鉴定出，但在粪便中没有检测到。消除主要通过粪便（88%到95%），这表明吸收较低；春日霉素没有在胆汁中排泄（没有发生肠肝循环）。

In the rat metabolism study, the mean radioactivity recovery 168 hours after exposure ranged from 91 to 97%, with the majority of the dose recovered within 48 hours in the feces (81.9-93.9%) and urine (1.26-3.07%). The maximum concentration found in the plasma of both males and females occurred approximately one hour after the administration of a single low or high dose. Between one and six hours after a single low or high dose, more kasugamycin accumulated in the kidneys, urinary bladder, and lymph nodes than in the blood, but after 168 hours, little or no kasugamycin was found in these tissues. The absorption and metabolism of kasugamycin in rats was limited (less than 5% of the dose) and was not affected by sex, dose level, or duration of dosing. The parent compound was the major component identified in the urine, feces, liver, kidney, and plasma. Minor amounts (less than 1% of the dose) of the metabolite kasuganobiosamine were identified in urine, liver, kidney, and plasma, but none was detected in the feces. Elimination occurred primarily in the feces (88 to 95%), suggesting low absorption; kasugamycin was not excreted in the bile (enterohepatic circulation did not occur).

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

毒性

• 大鼠急性经口LD₅₀为22000 mg/kg，小鼠为20000 mg/kg。每日以10000 mg/kg喂养大鼠90天，未引起异常。
• 对鱼虾低毒。

化学性质 它的盐酸盐为白色针状或片状结晶，熔点在206～210℃（202～204℃、236～239℃）之间。不溶于甲醇、乙醇、丙醇和苯等多种有机溶剂，易溶于水。

• 在酸性或中性介质中较稳定，在pH值5条件下，于50℃贮存10周效价没有下降；而在pH值为9的条件下，效价降至42.6%。

用途 低毒、内吸性杀菌剂。主要用于防治稻瘟病，在水稻抽穗期和灌浆期施药，通过内吸治疗作用发挥药效。

• 防治稻瘟病时，使用2%可湿性粉剂500～700倍液在发病初期喷施，每7～10天一次。叶瘟、穗颈瘟各喷两次。

用途 该品是农医两用抗菌素。春雷霉素对稻瘟病菌有强烈的抑制作用。

• 40μg/ml（每亩用量4g）喷雾，可显著治疗和保护苗瘟、叶瘟、穗颈瘟，防治效果达70-85%，略优于或相当于600倍稻瘟净。
• 与稻瘟净混用时，可将防治效果提高到97%并延缓抗菌株的产生。

生产方法 发酵生产的工艺过程如下：

1. 发酵
2. 培养基成分
3. 生物测定
4. 提取

春雷霉素由我国小金色放线菌（Actinomycetes microaurous)或日本放线菌（Streptomyces kasugaensis）产生。

生产过程如下：

• 砂土管菌种的制备：将预先处理好的砂和土以3:2或2:1均匀混合，分装于玻璃试管中，加棉塞并用纱布包扎，高压蒸汽灭菌后选择孢子生长丰满的斜面菌种，加无菌水制成孢子悬液，在砂土管中干燥封口，置于2～5℃水箱保存。
• 斜面孢子制备：在试管或茄形瓶中斜面培养，加棉塞高压蒸汽灭菌后用接种环沾取少许砂土孢子涂于斜面上，于28℃培养11～12天至表面孢子丰满呈粉灰色或粉红色。
• 种瓶培养：在无菌室用接种铲刮取少许斜面孢子接入已灭菌的装有培养基的种子瓶中，在28℃恒温振荡培养30小时左右，镜检菌丝量多、粗壮旺盛且无杂菌时即可移种。
• 种子罐：在300L种子罐中加入150L自来水，灭菌操作后接入菌种并保持罐温及通气量，在28℃条件下连续搅拌20～24小时pH值上升至6.5以上。
• 提炼过程：春雷霉素的提炼可加入一定量草酸使pH值降至3～4，在65～70℃加热，板框压滤除去滤渣后，滤液真空薄膜浓缩至浓度为20000～220000r/mL，加入0.2%苯甲酸钠作为防腐剂即可包装；也可采用浓缩液经盐酸调节pH<3后加入7倍体积、40～45℃的盐酸乙醇溶液中，析出白色絮状结晶，冷却滤出固体并进行红外干燥。

类别

• 有毒物品

毒性分级

• 低毒

急性毒性

• 口服-大鼠 LD50: 11400 毫克/公斤
• 口服-小鼠 LD50: 21000 毫克/公斤

可燃性危险特性

• 燃烧产生有毒氮氧化物和氯化物烟雾；注射副作用：影响血液

储运特性

• 通风低温干燥

灭火剂

• 干粉、泡沫、沙土、二氧化碳、雾状水

文献信息

• Methods and compositions relating to the treatment of fibrosis
  申请人：BROWN UNIVERSITY

  公开号：US11219630B2

  公开（公告）日：2022-01-11

  Described herein are methods of treating fibrosis and fibrotic diseases with certain aminoglycosides, e.g., kasugamycin derivatives thereof.

  本文介绍了用某些氨基糖苷类药物，如卡苏霉素衍生物治疗纤维化和纤维化疾病的方法。
• TREATMENT OF LYMPHANGIOLEIOMYOMATOSIS
  申请人：THE BRIGHAM AND WOMEN'S HOSPITAL, INC.

  公开号：US20160022706A1

  公开（公告）日：2016-01-28

  Embodiments disclosed herein provide compositions and methods for treating lymphangioleiomyomatosis (LAM) comprising inhibiting COX overexpression and prostaglandin over production by administering at least one COX inhibitor and/or prostaglandin biosynthetic pathway inhibitors. Lymphangioleiomyomatosis (LAM) is a rare lung disease. Some LAM occurances are associated with mutations in the tuberous sclerosis complex (TSC) locus. LAM occurs almost exclusively in women, usually of childbearing age.
• TREATMENT OF MTOR HYPERACTIVE RELATED DISEASES AND DISORDERS
  申请人：THE BRIGHAM AND WOMEN'S HOSPITAL, INC.

  公开号：US20160129030A1

  公开（公告）日：2016-05-12

  Embodiments disclosed herein provide compositions and methods for treating cancer having deregulated mTOR signaling or mTOR hyperactivity, e.g., lymphangioleiomyomatosis (LAM), LAM/TSC or treating and/or management of tuberous sclerosis complex (TSC). Such methods and compositions comprise at least one compound selected from the group consisting of nateglinide, Z-L-Phe chloromethyl ketone, clemastine fumarate, supercinnamaldehyde, practolol, fluvastatin Na, sulindac, BIO, amorolfine, spectinomucin, sibutramine HCl, nelfinavir mesylate, moroxydine HCl, nicotine ditartrate, trequinsin, meglumine, tizanidine HCl, CGP-74514A hydrochloride, tioconazole, TOVOK™ (afatinib), or kasugamycin.
• METHODS AND COMPOSITIONS RELATING TO THE TREATMENT OF FIBROSIS
  申请人：BROWN UNIVERSITY

  公开号：US20210128595A1

  公开（公告）日：2021-05-06

  Described herein are methods of treating fibrosis and fibrotic diseases with certain aminoglycosides, e.g., kasugamycin derivatives thereof.
• [EN] TREATMENT OF LYMPHANGIOLEIOMYOMATOSIS<br/>[FR] TRAITEMENT DE LA LYMPHANGIOLÉIOMYOMATOSE
  申请人：BRIGHAM & WOMENS HOSPITAL

  公开号：WO2014137978A1

  公开（公告）日：2014-09-12

  Embodiments disclosed herein provide compositions and methods for treating lymphangioleiomyomatosis (LAM) comprising inhibiting COX overexpression and prostaglandin over production by administering at least one COX inhibitor and/or prostaglandin biosynthetic pathway inhibitors. Lymphangioleiomyomatosis (LAM) is a rare lung disease. Some LAM occurances are associated with mutations in the tuberous sclerosis complex (TSC) locus. LAM occurs almost exclusively in women, usually of childbearing age.