leurocristine | 57-22-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 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
• 英文名称: leurocristine
• 英文别名: vincristine；methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 57-22-7
• 化学式: C₄₆H₅₆N₄O₁₀
• 分子量: 824.971
• InChiKey: OGWKCGZFUXNPDA-CUGARIAGSA-N

物化性质

• 熔点：
  211-216 ºC
• 比旋光度：
  D25 +17°; D25 +26.2° (ethylene chloride)
• 沸点：
  761.92°C (rough estimate)
• 密度：
  1.1539 (rough estimate)
• 溶解度：
  溶于氯仿、二氯甲烷、乙酸乙酯、DMSO、丙酮等。
• 物理描述：
  Vincristine appears as a white crystalline solid. Melting point 218°C. Used as an antineoplastic.
• 颜色/状态：
  Blades from methanol
• 稳定性/保质期：
  STERILE SOLN IN EITHER H2O OR PHYSIOLOGICAL SALINE STORED IN REFRIGERATOR FOR UP TO 2 WK WITHOUT SIGNIFICANT LOSS OF POTENCY
• 旋光度：
  Specific optical rotation: +17 deg at 25 °C/D; +26.2 deg at 25 °C/D (ethylene chloride); max absorption (ethanol): 220, 255, 296 nm (log molar absorptivity = 4.65, 4.21, 4.18)
• 分解：
  When heated to decomposition it emits toxic fumes of oxides of nitrogen.
• 解离常数：
  pKa: 5.0, 7.4 in 33% dimethylformamide

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  60
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  171
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

静脉注射[放射性同位素标记的]长春新碱后，72小时内，69%的放射性物质在粪便中回收，12%在尿液中回收。大约一半是以代谢物的形式存在，其紫外光谱表明长春新碱二聚体保持完整。胆瘘患者显示出完整的药物（46.5%）和代谢物（53.5%）的广泛胆汁排泄。观察结果提示胆汁-粪便途径在排泄中占主导地位。

After iv administration of ... (3)H vincristine, 69% of radioactivity was recovered in feces and 12% in urine over 72 hr period. Approx half ... was in form of metabolites, whose UV spectrum suggested that vincristine dimer was intact. Patients with biliary fistula showed extensive biliary excretion of intact drug (46.5%) & of metabolites (53.5%). Observations suggest that biliary-fecal route ... predominate in excretion ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

长春新碱的代谢命运尚未明确确定；该药物似乎被广泛代谢，可能是在肝脏中，但代谢的程度不清楚，因为药物在体内也显然会分解。

The metabolic fate of vincristine has not been clearly determined; the drug appears to be extensively metabolized, probably in the liver, but the extent of metabolism is not clear since the drug also apparently undergoes decomposition in vivo.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：大多数来源认为，在母亲抗肿瘤药物治疗期间，母乳喂养是禁忌的。由于长春新碱的半衰期较长，可能在长春新碱治疗后恢复母乳喂养是不切实际的。化疗可能会不利地影响母乳的正常微生物组和化学成分。 ◉ 对哺乳婴儿的影响：在一个4个月大的婴儿中，中性粒细胞减少可能是由于母亲在连续6周每周静脉注射800毫克环磷酰胺、2毫克长春新碱静脉注射和每天30毫克泼尼松龙口服的最后9天由环磷酰胺引起的。中性粒细胞减少持续至少12天，并伴有短暂的腹泻。长春新碱对中性粒细胞减少的贡献无法确定。 一名妇女在怀孕27周时被诊断出患有B细胞淋巴瘤。在34 4/7周时诱导分娩，并在分娩后第2天开始使用标准的利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松治疗方案，剂量不明确，每21天一个周期。她在每个周期的前10天泵奶并丢弃，用捐赠的奶喂养婴儿，然后在下一个治疗周期前的剩余10天母乳喂养婴儿。根据长春新碱的大约3个半衰期来确定10天的母乳喂养禁食期。在完成4个周期的化疗后，她的婴儿据报道健康无并发症地发育。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vincristine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants:In a 4-month-old, neutropenia was probably caused by cyclophosphamide in a mother 9 days after the last of 6 weekly doses of 800 mg cyclophosphamide intravenously, 2 mg vincristine intravenously and daily doses of 30 mg of prednisolone orally. Neutropenia persisted at least 12 days and was accompanied by a brief episode of diarrhea. The contribution of vincristine to the neutropenia cannot be determined. A woman was diagnosed with B-cell lymphoma at 27 weeks of pregnancy. Labor was induced at 34 4/7 weeks and treatment was begun with a standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in unspecified doses on a 21-day cycle, starting on day 2 postpartum. She pumped and discarded her milk and fed her infant donor milk for the first 10 days of each cycle and then breastfed her infant for the remaining 10 days before the next treatment cycle. The 10-day period of breastfeeding abstinence was determined by using about 3 half-lives of vincristine. After completion of 4 cycles of chemotherapy, her infant was reportedly healthy and developing without any complications. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

硫酸长春新碱与伊曲康唑（已知是代谢途径的抑制剂）同时给药据报道会导致神经肌肉副作用更早出现和/或增加严重程度（见不良反应）。这种相互作用被认为与抑制长春新碱的代谢有关。

Concurrent administration of vincristine sulfate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side effects (see Adverse Reactions). This interaction is presumed to be related to inhibition of the metabolism of vincristine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

口服或静脉注射苯妥英钠与包括硫酸长春新碱在内的抗肿瘤化疗方案同时给药，据报道会降低抗惊厥药物的血液水平并增加癫痫发作活动。剂量调整应基于连续的血药浓度监测。硫酸长春新碱对此相互作用的贡献尚不确定。这种相互作用可能是由苯妥英钠吸收减少以及其代谢和排泄速率增加所导致。

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vincristine sulfate has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vincristine sulfate to this interaction is not certain. The interaction may result from reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

牛脑神经节苷脂对长春新碱神经毒性的影响在10天鸡胚背根神经节细胞的分离培养中进行了研究。药物的作用通过计算具有神经突起的细胞数量或单个具有神经突起的细胞中神经突起的总长度来量化。长春新碱（1至1000 pg/mL）的给药抑制了细胞的神经突起生长，而神经节苷脂（10至1000 ug/mL）以浓度依赖性方式保护细胞免受这种抑制。电子显微镜揭示了长春新碱诱导神经突起中的微管断裂和纵向定向错误，并显示了神经节苷脂对这种损害作用的防护。结果表明，外源性给予神经节苷脂可以减轻长春新碱在体外的神经毒性。

The effects of bovine brain gangliosides on the neurotoxicity of vincristine were investigated in dissociated cultures of dorsal root ganglion cells from 10 day chick embryos. The effects of the drugs were quantified as the numbers of neurite bearing cells or total neurite length in individual neurite bearing cells. The administration of vincristine (1 to 1000 pg/mL) inhibited neurite outgrowth from the cells, whereas gangliosides (10 to 1000 ug/mL) protected them against this inhibition in a concentration dependent manner. Electron microscopy revealed vincristine induced fragmentation and longitudinal disorientation of microtubules in neurites and showed the protection by gangliosides against such damaging effects. Results show that exogenous administration of gangliosides attenuates the neurotoxicity of vincristine in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维拉帕米已被证明能够在体外和体内克服P388白血病对长春新碱的获得性耐药。为了研究这种作用的特异性，本研究探讨了在慢性淋巴细胞白血病患者淋巴细胞、T急性淋巴细胞白血病细胞系（GM 3639）和8名正常健康志愿者的外周血淋巴细胞中添加维拉帕米对长春新碱细胞毒性的影响。使用差异染色细胞毒性分析，证明了在1 uM浓度下，维拉帕米能够增强长春新碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，浓度为0.04-0.25 ug/L。然而，在对对照组外周血淋巴细胞的细胞毒性方面，并未观察到增强作用。数据显示，维拉帕米优先增强长春新碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，但对外周血淋巴细胞的细胞毒性没有增强作用。

Verapamil has been shown to overcome acquired drug resistance to vincristine in P388 leukemia both in vitro and in vivo. To study the selectivity of this action, the effect of addition of verapamil on the cytotoxicity of vincristine was studied using lymphocytes from eight patients with chronic lymphocytic leukemia, lymphoblasts from a T-acute lymphoblastic leukemia cell line (GM 3639), and peripheral blood lymphocytes from eight normal healthy volunteers. Using the differential staining cytotoxicity assay, it was demonstrated that verapamil at 1 uM concentration potentiated the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells in concentrations of 0.04-0.25 ug/L. There was however, no enhancement of cytotoxicity noted against the control peripheral blood lymphocytes. The data demonstrate that verapamil preferentially enhances the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells but no enhancement of cytotoxicity is seen against peripheral blood lymphocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

中枢神经系统白血病在接受长春新碱治疗且血液学缓解的患者中的发展被解释为证据，表明长春新碱很难通过血脑屏障。长春新碱可以以比静脉给药大几倍的剂量注入肿瘤的动脉血液供应中，而毒性相当；因此，局部吸收或破坏非常迅速。长春花生物碱主要通过肝脏排入胆汁。

Development of CNS leukemia in patients receiving vincristine and in hematological remission has been interpreted as evidence that ... /vincristine/ penetrates blood-brain barrier poorly. Vincristine ... can be infused into arterial blood supply of tumors in doses several times larger than those that can be admistered iv with comparable toxicity; thus either local uptake or destruction is very rapid. Vinca alkaloids appear to be excreted primarily by liver into bile.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

注射后的头几个小时内，狗和猴子的尿排泄量都很低。在两者中，药物分布到了大多数组织中，但浓度最高的发现于肺、肾、脾、胰腺和肝脏。在猴子中，长春新碱及其代谢物迅速从血浆进入脑脊液，形成持续数日的低药物浓度。

Urinary excretion ... over first few hr after injection was ... low in dogs and monkeys. In both ... the drug was distributed to most tissues, but highest concentrations ... found in lung, kidney, spleen, pancreas and liver. In monkeys, vincristine and its metabolites rapidly entered cerebrospinal fluid from plasma to form low concentrations of drug, which persisted for several days.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸长春新碱从胃肠道的吸收是不可预测的。在肾功能和肝功能正常的患者中，快速静脉注射2毫克剂量的硫酸长春新碱后，血药浓度会立即达到大约0.19-0.89微摩尔/升的峰值，并且药物会迅速从血液中清除。当使用相同剂量的药物时，与快速静脉注射相比，连续静脉输注的血药浓度-时间曲线下面积有所增加。

Vincristine sulfate is unpredictably absorbed from the Gl tract. Following rapid iv injection of a 2 mg dose of vincristine in patients with normal renal and hepatic function, peak serum drug concentrations of approximately 0.19-0.89 uM occur immediately and the drug is rapidly cleared from serum. The area under the serum vincristine concentration time curve has been shown to be increased following continuous iv infusion compared with rapid iv injection of the drug when comparable doses are administered.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长春新碱及其代谢物（和/或分解产物）在人体组织和液体中的分布尚未被完全表征，但药物在静脉给药后迅速且广泛分布。分布到组织中的药物紧密结合但可逆。长春新碱及其代谢物（和/或分解产物）迅速且广泛地分布到胆汁中，在快速静脉注射药物后2-4小时内胆汁中达到峰值浓度。长春新碱及其代谢物（和/或分解产物）在快速静脉注射后很少穿过血脑屏障，通常不会在脑脊液中以细胞毒浓度出现。

Distribution of vincristine and its metabolites (and/or decomposition products) into human body tissues and fluids has not been fully characterized, but the drug is rapidly and apparently widely distributed following iv administration. Drug that is distributed into tissues is tightly but reversibly bound. Vincristine and its metabolites (and/or decomposition products) are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2-4 hr after rapid iv injection of the drug. Vincristine and its metabolites (and/or decomposition products) cross the blood brain barrier poorly following rapid iv injection and generally do not appear in the CSF in cytotoxic concentrations.

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)

制备方法与用途

理化性质

长春新碱（Vincristine, Oncovin, VCR）是从夹竹桃科植物长春花中提取出的生物碱。它具有显著的抗肿瘤作用，目前作为临床抗肿瘤药物使用。在甲醇中重结晶时形成针状结晶，熔点为211～216℃，比旋光度+42°（氯仿）。

长春新碱、长春碱是长春花中具有抗肿瘤活性的二聚吲哚类生物碱，在抗击癌症方面表现出显著疗效。

发现历史

加拿大医生罗伯特·诺布尔（Robert Noble）是一位研究糖尿病的医学家。他的哥哥克拉克·诺布尔（Clark Noble，对发现胰岛素做出了巨大贡献）听说“牙买加人将长春花当作茶来治疗糖尿病”，并将这一消息告知了罗伯特，并寄了一些样品给他。和大多数药物学家一样，罗伯特也是通过民间医学获取信息，然后经过科学验证，分离出有效的化合物以开发新药。

通过给小白鼠和兔子注射长春花提取液，他们发现长春花并不能降低血糖浓度。然而令人惊讶的是，灭菌的长春花提取液却导致了小白鼠肝脏和肾脏脓肿。进一步研究揭示，长春花提取液破坏了小白鼠的免疫系统，并直接损害了脊髓造血细胞，从而降低了血液中负责免疫的能力。

敏锐的罗伯特很快意识到，这种成分可以杀死白细胞。因此，他认为长春花对治疗白血病具有潜在疗效。白血病是由骨髓异常导致不正常白血球大量繁殖所致。

在敏锐地认识到长春花可能对白血病有潜在疗效后，罗伯特邀请了化学家查尔斯·比尔（Charles Beer）加入研究团队，共同着手分离长春花中的特殊成分。1958年，他们最终得到一个具有活性的生物碱，并命名为长春新碱（Vinblastine）。后来与美国著名医药公司Eli Lilly合作研发，成功推出抗癌药物——长春新碱，其疗效比长春花碱更好，是治疗白血病的首选化疗药物，特别对急性淋巴性白血病、霍奇金氏淋巴瘤等癌症有显著效果。

药理作用

长春新碱能抗癌，疗效比长春碱约高10倍。它可用于治疗急性淋巴细胞性白血病，对其他急性白血病、何杰金氏病、淋巴肉瘤、网状细胞肉瘤和乳腺癌也有一定疗效。长春新碱与长春花碱（Vinblastine）、泛洛洛新及泛洛洗汀等一起存在于蔓长春花中的生物碱具有使细胞分裂（有丝分裂）在中期停止的作用，这类似于化疗药物的效果。

适应症

• 急性白血病，尤其是儿童急性白血病
• 恶性淋巴瘤
• 生殖细胞肿瘤
• 小细胞肺癌、尤文肉瘤、肾母细胞瘤、神经母细胞瘤
• 乳腺癌、慢性淋巴细胞白血病、消化道癌、黑色素瘤及多发性骨髓瘤等

典型不良反应

• 骨髓功能抑制
• 消化道反应
• 神经系统毒性：四肢麻木、腱反射迟钝或消失、外周神经炎、便秘、麻痹性肠梗阻、运动神经和感受神经及脑神经症状
• 血栓性静脉炎，注射时漏至血管外可造成局部坏死

化学性质

长春新碱是白色结晶体，易溶于甲醇、乙醇、DMSO等有机溶剂。

用途

天然植物抗肿瘤药，用于治疗急性白血病和恶性淋巴瘤、小细胞肺癌及乳腺癌。

反应信息

• 作为产物：
  描述：

  vinblastine sulfate 在 chromium(VI) oxide 、 乙酸酐 、 溶剂黄146 作用下， 以 水 、 丙酮 为溶剂， 反应 0.13h， 生成 leurocristine 、
  参考文献：
  名称：

  一种半合成硫酸长春新碱的方法

  摘要：

  本发明公开了一种半合成硫酸长春新碱的方法，包括以下步骤：以硫酸长春碱粗品为原料，先将其进行精制得到高纯度，经氧化、甲酰化生成得到长春新碱粗品，通过氧化铝柱层析纯化，直接成盐得到硫酸长春新碱。本工艺操作简单，后处理容易，成盐产品无需再进行精制就能得到纯度达97％以上，收率达到40‑50％，大大降低了成本，具有生产可行性且有很高经济价值。

  公开号：

  CN107880064A

文献信息

• Method of treating cancers with SAHA and pemetrexed
  申请人：Pluda James

  公开号：US20070117815A1

  公开（公告）日：2007-05-24

  The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent. The HDAC inhibitor and the anti-cancer agent may be administered to comprise therapeutically effective amounts. In various aspects, the effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.

  本发明涉及一种治疗需要的受试者癌症的方法，通过向需要的受试者施用一定量的组蛋白去乙酰化酶（HDAC）抑制剂或其药用可接受的盐或水合物的第一量，以及一定量的抗癌药物。HDAC抑制剂和抗癌药物可以被施用以包含治疗有效量。在各种方面，HDAC抑制剂和抗癌药物的效果可能是相加的或协同的。
• 一种半合成硫酸长春新碱的方法
  申请人：广州普星药业有限公司

  公开号：CN107880064A

  公开（公告）日：2018-04-06

  本发明公开了一种半合成硫酸长春新碱的方法，包括以下步骤：以硫酸长春碱粗品为原料，先将其进行精制得到高纯度，经氧化、甲酰化生成得到长春新碱粗品，通过氧化铝柱层析纯化，直接成盐得到硫酸长春新碱。本工艺操作简单，后处理容易，成盐产品无需再进行精制就能得到纯度达97％以上，收率达到40‑50％，大大降低了成本，具有生产可行性且有很高经济价值。
• FATTY ALCOHOL DRUG CONJUGATES
  申请人：Swindell S. Charles

  公开号：US20080090803A1

  公开（公告）日：2008-04-17

  The invention provides conjugates of fatty alcohols and pharmaceutical agents useful in treating cancer, viruses, psychiatric disorders. Compositions, pharmaceutical preparations, and methods of preparation of the fatty alcohols-pharmaceutical agent conjugates are provided.
• FATTY AMINE DRUG CONJUGATES
  申请人：Swindell Charles S.

  公开号：US20080153899A1

  公开（公告）日：2008-06-26

  The invention provides conjugates of fatty amines and pharmaceutical agents useful in treating cancer, viruses, psychiatric disorders. Compositions, pharmaceutical preparations, and methods of preparations of the fatty amine-pharmaceutical agent conjugates are provided.
• SHORT TAT OLIGOMERS FOR DRUG DELIVERY
  申请人：The Trustees of Columbia University in the City of New York

  公开号：US20200338202A1

  公开（公告）日：2020-10-29

  Trans-activating transcription (TAT) factor peptide oligomers coupled with functional agents can selectively complex to the anionic surface of cancerous cells. The TAT conjugates can be delivered to the locus of the tumors using intra-arterial injection during transient blood flow arrest.