ent-(-)-vinblastine | 865-21-4

• 物质功能分类: 分析化学 - 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
• 英文名称: ent-(-)-vinblastine
• 英文别名: (+)-leurosidine；(+)-vinblastine；vinblastine；4-acetoxy-3-hydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester；Vincaleukoblastin；Methyl 11-acetyloxy-12-ethyl-4-(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)-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 865-21-4；15228-71-4；61949-65-3；72346-48-6；72346-49-7；72401-36-6；74345-28-1；74741-43-8
• 化学式: C₄₆H₅₈N₄O₉
• 分子量: 810.988
• InChiKey: JXLYSJRDGCGARV-UHFFFAOYSA-N

物化性质

• 熔点：
  211-216°
• 比旋光度：
  D23 -32° (c = 0.88 in methanol)
• 沸点：
  755.65°C (rough estimate)
• 密度：
  1.1325 (rough estimate)
• 溶解度：
  可溶于氯仿、二氯甲烷、二甲基亚砜、甲醇
• 颜色/状态：
  Solvated needles from methanol
• 蒸汽压力：
  1.03X10-27 mm Hg at 25 °C (est)
• 稳定性/保质期：
  SOLN MAY BE STORED IN REFRIGERATOR FOR PERIODS OF 30 DAYS WITHOUT SIGNIFICANT LOSS OF POTENCY /VINBLASTINE SULFATE/
• 旋光度：
  Specific optical rotation: -32 deg at 23 °C/D ( c = 0.88 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of oxides of nitrogen.
• 解离常数：
  pKa1 = 5.4; pKa2 = 7.4

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：
  9.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  154
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

长春碱据报道会被广泛代谢，主要在肝脏中，代谢成去乙酰长春碱，后者在重量基础上比原化合物更活跃。

Vinblastine is reported to be extensively metabolized, primarily in the liver, to desacetylvinblastine, which is more active than the parent compound on a weight basis.

来源:Hazardous Substances Data Bank (HSDB)

代谢

由于主要的排泄途径可能是通过胆汁系统，当存在肝脏排泄功能不足时，这种药物的毒性可能会增加。已证实长春花碱的代谢是通过肝脏细胞色素P450同工酶CYP 3A亚家族介导的。在肝功能不全的患者或同时服用这些同工酶的强效抑制剂（如红霉素）的患者中，这种代谢途径可能会受损。

Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期间使用总结：大多数资料认为，在母体抗肿瘤药物治疗期间，哺乳是禁忌的。由于长春碱疗法的半衰期较长，可能在治疗后恢复哺乳是不切实际的。化疗可能会不利地影响母乳的正常微生物组和化学成分。在怀孕期间接受化疗的妇女更可能有困难哺乳她们的婴儿。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 对泌乳和母乳的影响：一名在怀孕第二季度被诊断患有霍奇金淋巴瘤的妇女在第三季度怀孕期间接受了3轮化疗，并在产后4周恢复了化疗。在重新开始化疗后的16周内，收集了她在化疗前后15至30分钟的乳汁样本。治疗方案包括每2周一次，2小时内给予多柔比星40毫克，博来霉素16单位，长春碱9.6毫克和达卡巴嗪600毫克。将她的乳汁微生物群和代谢概况与8位未接受化疗的健康妇女进行了比较。患者的母乳微生物群与健康妇女明显不同，Acinetobacter sp., Xanthomonadacae 和 Stenotrophomonas sp. 增加，而 Bifidobacterium sp. 和 Eubacterium sp. 减少。在接受治疗的妇女的母乳中，许多化学成分也有显著差异，尤其是DHA和肌醇减少。 对同一中心在怀孕第二或第三季度接受癌症化疗的74位妇女进行了电话随访研究，以确定她们产后是否成功哺乳。只有34%的妇女能够完全用母乳喂养她们的婴儿，而66%的妇女报告遇到哺乳困难。这与其他22位在怀孕期间被诊断但在未接受化疗的母亲中的91%的哺乳成功率相比。其他具有统计学意义的相关性包括：1.有哺乳困难的母亲平均接受了5.5个周期的化疗，而没有困难的母亲平均接受了3.8个周期；2.有哺乳困难的母亲在怀孕期间平均提前3.4周接受了她们的第一个化疗周期。在接受含有长春新碱方案治疗的6位妇女中，有5位有哺乳困难。

◉ 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 vinblastine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased. A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 6 women who received a vincristine-containing regimen, 5 had breastfeeding difficulties.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

在同时服用已知抑制肝细胞色素P450同工酶CYP 3A亚家族药物代谢的药物的患者，或肝功能不全的患者中应谨慎。与这种代谢途径的抑制剂同时使用长春碱硫酸盐可能会导致副作用更早出现和/或增加严重性。

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时口服或静脉注射苯妥英钠和包括硫酸长春碱在内的抗肿瘤化疗组合已报告降低了抗惊厥药物的血液水平，并增加了癫痫发作活动。

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

评估长春碱和重组干扰素-β之间可能存在的协同作用，使用中效分析法。组合指数的计算显示出小于1的值（表示协同作用），在四种不同的肾细胞癌细胞系中，药物引起的生长抑制的广泛范围内。观察到的协同作用程度无法从形态、倍增时间或肾细胞癌细胞系对长春碱和重组干扰素-β的相对敏感性来预测。长春碱与重组干扰素-β在组合中的最佳比例似乎接近于每种药物浓度产生50%生长抑制的比例。虽然长春碱和重组干扰素-β同时存在于培养液中并不是展示协同作用的必要条件，但重组干扰素-β的最小暴露时间被确定为7天。在2.25 ng/mL的重组干扰素-β中生长4天后，肾细胞癌细胞系对氚标记的长春碱的摄取增加，但排出并未增加。中效分析法可以显示长春碱和重组干扰素-β的作用机制独立，并且给出了在广泛药物效果范围内潜在协同作用的指示。这种方法可能在选择干扰素和抗肿瘤药物组合进行临床研究时证明是有用的。

Potential synergistic interactions between vinblastine and recombinant interferon-beta were assessed using median effect analysis. Calculation of the combination index demonstrated values less than 1 (indicating synergy) over a wide range of drug induced growth inhibition for each of four different renal carcinoma cell lines. The degree of synergy observed could not be predicted from the morphology, doubling time, or relative sensitivity of the renal carcinoma cell lines to vinblastine and recombinant interferon-beta. The optimal ratio of vinblastine to recombinant interferon-beta in the combination appeared to be close to the ratio of the concn of each agent which yielded a 50% inhibition of growth. Although simultaneous presence of vinblastine and recombinant interferon-beta in the culture medium was not required to demonstrate a synergistic effect, the minimum exposure time for recombinant interferon-beta was determined to be 7 days. The uptake but not the egress of tritiated vinblastine into renal carcinoma cell line cells was enhanced after growth for 4 days in 2.25 ng/mL of recombinant interferon-beta. Median effect analysis can be shown to be independent of the mechanism of action of vinblastine and recombinant interferon-beta and gives an indication of potential synergistic interactions over a wide range of drug effects. This method may prove useful in the selection of combinations of IFNs and antitumor drugs for clinical study.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一名艾滋病毒感染者在接受ABVD（多柔比星、博来霉素、长春碱、达卡巴嗪）化疗和基于洛匹那韦-利托那韦的抗逆转录病毒治疗期间，因治疗霍奇金淋巴瘤IVB期而出现了严重威胁生命的粒细胞减少症。通过在化疗给药期间中断洛匹那韦-利托那韦来管理长春碱和洛匹那韦-利托那韦的相互作用，经过六个疗程后，患者实现了完全缓解和免疫病毒学上的成功。

A HIV infected patient was treated for stage IVB Hodgkin's lymphoma by ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and lopinavir-ritonavir based antiretroviral therapy inducing profound life-threatening neutropenia. Vinblastine and lopinavir-ritonavir interaction was managed with lopinavir-ritonavir interruption around chemotherapy administration, with complete remission and immunovirological success after six cycles.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸长春碱从胃肠道吸收不可预测。静脉给药后，药物会迅速从血液中清除并分布到身体组织中。硫酸长春碱很难穿过血脑屏障，在治疗浓度下不会出现在脑脊液中。

Vinblastine sulfate is unpredictably absorbed from the GI tract. Following iv administration, the drug is rapidly cleared from the blood and distributed into body tissues. Vinblastine crosses the blood brain barrier poorly and does not appear in the CSF in therapeutic concentrations.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

中央室的体积占体重的70%，这很可能反映了药物与血液有形成分的快速组织结合。广泛的可逆组织结合发生。注射后48小时和72小时，体内储存量较低。

The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在向人类癌症患者注射放射性同位素标记的长春碱后，发现10%的放射性活性出现在粪便中，14%出现在尿液中；其余活性未被计算在内。在狗身上的类似研究表明，在9天内，30%至36%的放射性活性出现在胆汁中，12%至17%出现在尿液中。在大鼠身上的类似研究发现，注射后2小时，放射性活性的最高浓度出现在肺、肝、脾和肾中。

Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36% of radioactivity was found in the bile and 12% to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen, and kidney 2 hours after injection.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这种药物是否排泄入人乳中尚不清楚。

It is not known whether this drug is excreted in human milk.

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)
• 储存条件：
  -20°C

制备方法与用途

长春碱是从长春花中提取的药物，具有抗癌作用，广泛应用于临床抗肿瘤治疗，具有很高的药用价值。

化学性质 长春碱为白色结晶体，可溶于甲醇、乙醇和DMSO等有机溶剂，来源于长春花。

用途 主要用于治疗恶性淋巴瘤。

反应信息

• 作为产物：
  描述：

  (+)-anhydrovinblastine 在 sodium tetrahydroborate 、 air 作用下， 以 水 为溶剂， 反应 0.5h， 生成 ent-(-)-vinblastine
  参考文献：
  名称：

  Catharanthine 和 Vindoline 的直接偶联以提供长春碱：(+)-andent-(-)-Vinblastine 的全合成

  摘要：

  详细介绍了角黄素与文多林直接偶联以提供长春碱的关键机制和标记研究。在 Fe(III) 促进的偶联反应通过产生假定的角黄素胺自由基阳离子引发后，该阳离子经历随后的氧化断裂和与文多林的非对映选择性偶联，将所得反应混合物添加到 Fe(III)-NaBH4/空气溶液中C15'-C21' 双键的氧化和中间体亚胺离子的还原直接提供长春碱 (43%) 和亮氨酸 (23%)，其天然存在的 C21' 醇异构体。仅具有天然C16'立体化学的偶联产物的产率接近或超过80%，异构C21'醇的综合产率为66%。

  DOI：

  10.1021/ja078192m

文献信息

• Direct Coupling of Catharanthine and Vindoline to Provide Vinblastine:  Total Synthesis of (+)- and <i>ent</i>-(−)-Vinblastine
  作者：Hayato Ishikawa、David A. Colby、Dale L. Boger

  DOI：10.1021/ja078192m

  日期：2008.1.1

  a presumed cantharanthine amine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH4/air solution leads to oxidation of the C15'-C21' double bond and reduction of the intermediate iminium ion directly providing vinblastine (43%) and leurosidine (23%), its naturally occurring C21'

  详细介绍了角黄素与文多林直接偶联以提供长春碱的关键机制和标记研究。在 Fe(III) 促进的偶联反应通过产生假定的角黄素胺自由基阳离子引发后，该阳离子经历随后的氧化断裂和与文多林的非对映选择性偶联，将所得反应混合物添加到 Fe(III)-NaBH4/空气溶液中C15'-C21' 双键的氧化和中间体亚胺离子的还原直接提供长春碱 (43%) 和亮氨酸 (23%)，其天然存在的 C21' 醇异构体。仅具有天然C16'立体化学的偶联产物的产率接近或超过80%，异构C21'醇的综合产率为66%。