长春素 | 23360-92-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 长春花生物碱
• 中文名称: 长春素
• 中文别名: 长春罗新；环氧长春碱
• 英文名称: Leurosin
• 英文别名: 4β-acetoxy-3'α,4'-epoxy-3-hydroxy-16-methoxy-(4'αH)-vincaleukoblast-6-ene-23,22'-dioic acid dimethyl ester；leurosine；methyl (13S,15S,16R,18S)-13-[(1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-10-hydroxy-5-methoxy-10-methoxycarbonyl-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraen-4-yl]-18-ethyl-17-oxa-1,11-diazapentacyclo[13.4.1.04,12.05,10.016,18]icosa-4(12),5,7,9-tetraene-13-carboxylate
• CAS: 23360-92-1
• 化学式: C₄₆H₅₆N₄O₉
• 分子量: 808.972
• InChiKey: LPGWZGMPDKDHEP-NVDFJPPOSA-N

物化性质

• 熔点：
  202-205℃
• 密度：
  1.39
• 溶解度：
  In water, 7.56X10-3 mg/L at 25 °C (est)
• 蒸汽压力：
  6.23X10-26 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  59
• 可旋转键数：
  10
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  146
• 氢给体数：
  2
• 氢受体数：
  12

ADMET

毒理性

• 解毒与急救

保持呼吸道通畅，必要时辅助通气。如果出现昏迷、抽搐、低血压和心律失常，则进行治疗。使用甲氧氯普胺治疗恶心和呕吐，使用静脉晶体液治疗胃肠炎引起的液体丢失。对于骨髓抑制，应在经验丰富的血液学家或肿瘤学家的帮助下进行治疗。外渗：立即停止输液，并通过注射器的负压尽可能多地抽回液体。然后给予以下特定治疗：在区域上放置加热垫，间歇加热24小时；抬高肢体。局部注射透明质酸酶可能有益。不要使用冰袋。/对于/去污染，如果条件适当，口服活性炭。在小到中等摄入量后，如果可以迅速给予活性炭，则无需进行胃灌洗。由于这些药物的快速细胞内结合，透析和其他体外清除程序通常无效。/抗肿瘤药物/

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment: Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase may be beneficial. Do not use ice packs. /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

立即急救：确保已经进行了充分去污。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、气囊面罩装置或口袋面罩，按训练进行操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下位置），以保持呼吸道畅通并防止吸入。保持患者安静并维持正常体温。寻求医疗帮助。/毒物A和B/

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

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（如需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。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。在运输过程中，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、有强烈的呕吐反射且不流口水，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，用干性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、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。使用气囊面罩装置的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，考虑给予β受体激动剂，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%的生理盐水（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……。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

• 医疗监测

/抗癌药物的预防措施：/目前没有可用于常规监测人员接触危险药物证据的方法。检测诱变剂或染色体损伤的测试并非针对特定药物，且仅在控制性研究中具有价值。对尿液中存在危险药物的化学分析，在需要检测职业暴露的灵敏度水平上，仅限于少数药物，且尚未在商业上可用。/抗癌药物/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品运输编号：
  UN 1544
• 包装等级：
  II
• 危险类别：
  6.1(a)

反应信息

• 作为反应物：
  描述：

  长春素 在 bis(cyclopentadienyl)titanium (III) chloride 作用下， 以 四氢呋喃 为溶剂， 反应 0.25h， 以70%的产率得到脱水长春碱
  参考文献：
  名称：

  亮氨酸的选择性脱氧：简单获得脱水长春碱。

  摘要：

  据报道从母体生物碱亮氨酸开始直接获得脱水长春碱。首先在模型基板上优化了关键的脱氧步骤。但是，仅将低价的Cp2TiCl用于亮氨酸，结果令人满意。

  DOI：

  10.1021/jo0202942
• 作为产物：
  描述：

  脱水长春碱 在 horseradish peroxidase 作用下， 生成 长春素
  参考文献：
  名称：

  吲哚生物碱的生物合成。长春花植物的无细胞系统†

  摘要：

  长春花植物的无细胞系统被用于与吲哚生物碱的生物合成有关的各种研究。两种形式的基本构建单元-色胺（5）和secologanin（6）已显示已掺入生物碱长春花碱（7）中。在另一项研究中，该酶系统利用了catharanthine （18）和vindoline（7），并与重要的双吲哚生物中间体3'，4'-anhydrovinblastine1 （17）偶联。后者又被引入并转化为天然生物碱亮氨酸（8），凯瑟琳（9）和长春碱（10），从而提供有关这些复杂分子生物合成的信息。高压液相色谱法对酶混合物的分析揭示了参与18和7偶联的酶。

  DOI：

  10.1002/hlca.19820650716

文献信息

• Stereoselective Conversion of Anhydrovinblastine into Vinblastine Utilizing an Anti-vinblastine Monoclonal Antibody as a Chiral Mould
  作者：Tatsuya Shirahama、Takeyuki Kohno、Tomohiro Kaijima、Yasuo Nagaoka、Daisuke Morimoto、Kazumasa Hirata、Shinichi Uesato

  DOI：10.1248/cpb.54.665

  日期：——

  Dimeric indole alkaloid, anhydrovinblastine, which can be obtained from catharanthine and vindoline in a high yield, was converted stereoselectively into vinblastine through alternating oxidation-reduction with oxygen and NaBH(3)CN in the presence of anti-vinblastine monoclonal antibody.

  二聚吲哚生物碱，脱水长春碱，可以从catharanthine和长春花碱以高收率获得，通过在存在抗长春碱单克隆抗体的情况下，通过与氧气和NaBH（3）CN交替氧化还原，将立体选择性地转化为长春碱。
• Total synthesis of indole and dihydroindole alkaloids. XVII. The total synthesis of catharine and vinamidine (catharinine)
  作者：James P. Kutney、John Balsevich、Brian R. Worth

  DOI：10.1139/v79-270

  日期：1979.7.1

  (8) or leurosine (7) gave the natural product catharine (3). Potassium permanganate oxidation of 7 or 8 gave 3R-hydroxyvinamidine (19) whereas similar oxidation of 4′-deoxyleurosidine (29) gave the alkaloid vinamidine (4).

  16,18-二碳甲氧基分裂胺氧化得到环氧化物(6)和烯酰胺(9)。3',4'-脱氢长春碱 (8) 或亮氨酸 (7) 的类似氧化得到天然产物凯瑟琳 (3)。7 或 8 的高锰酸钾氧化得到 3R-羟基维脒（19），而 4'-脱氧鼠李糖苷（29）的类似氧化得到生物碱维脒（4）。
• Concise Synthesis of Anhydrovinblastine from Leurosine
  作者：Christophe Hardouin、Eric Doris、Bernard Rousseau、Charles Mioskowski

  DOI：10.1021/ol025560c

  日期：2002.4.1

  [reaction: see text] The Cp(2)TiCl-mediated deoxygenation of leurosine (1) afforded anhydrovinblastine (4) in good yield. Furthermore, as the reaction proceeded via a carbon-centered radical intermediate, this transient was also trapped by a hydrogen-atom donor to afford selectively reduced alkaloid 10.

  [反应：见正文] Cp（2）TiCl介导的亮氨酸（1）脱氧以良好的产率提供了脱水长春碱（4）。此外，随着反应通过以碳为中心的自由基中间体进行，该瞬变也被氢原子供体捕获，从而提供了选择性还原的生物碱10。
• Synthesis of Anti-Tumor Dimeric Indole Alkaloids in<i>Catharanthus roseus</i>Was Promoted by Irradiation with Near-Ultraviolet Light at Low Temperature
  作者：Mamiko ASANO、Kazuo HARADA、Tomoaki YOSHIKAWA、Takeshi BAMBA、Kazumasa HIRATA

  DOI：10.1271/bbb.90545

  日期：2010.2.23

  We have found that coupling between catharanthine and vindoline occurs non-enzymatically in the presence of flavin mononucleotide and manganese ions with near-ultraviolet light irradiation in vitro. The present study found that the concentrations of catharanthine and vindoline in Catharanthus roseus decreased and those of dimeric indole alkaloids increased under near-ultraviolet light at 4 °C. It indicates that this coupling reaction at 4 °C occurs non-enzymatically.

  我们发现，卡塔兰丁与紫堇碱之间的耦合在紫外线照射下，在存在黄素单核苷酸和锰离子的条件下，通过非酶促反应发生。本研究发现，在4°C的近紫外光照射下，卡塔兰丁和紫堇碱的浓度下降，而二聚体吲哚生物碱的浓度则增加。这表明在4°C下，耦合反应是通过非酶促方式发生的。
• Total synthesis of indole and dihydroindole alkaloids. XVI. Derivatives of vinblastine and vincristine: change of functionality in the vindoline unit
  作者：James P. Kutney、John Balsevich、Toshio Honda、Ping-Huang Liao、Herman P. M. Thieelier、Brian R. Worth

  DOI：10.1139/v78-420

  日期：1978.10.1

  Studies describing the preparation of various derivatives of vinblastine and vincristine are presented. Vindoline (3) is transformed into a series of derivatives and the latter via Polonovski-type coupling with catharanthine (2) provide the bisindole alkaloid derivatives of the vinblastine series. Selective Jones' oxidation transforms the vinblastine family into the corresponding vincristine derivatives.

  本文介绍了制备各种长春碱和长春花碱衍生物的研究。将长春花碱衍生物文多林（3）转化为一系列衍生物，然后通过与长春碱（2）进行波罗诺夫斯基型偶联反应，得到了长春碱系列的双吲哚生物碱衍生物。选择性的琼斯氧化将长春碱家族转化为相应的长春花碱衍生物。