长春氟宁 | 162652-95-1

• 物质功能分类: 生物化工 - 中草药成分
• 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: 长春氟宁
• 中文别名: 长春氟宁(二氟异长春花碱)；长春氟宁(二氟去甲脱水长春花碱)；20',20'-二氟-3',4'-二氢长春瑞滨
• 英文名称: vinflunine
• 英文别名: Javlor；methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-4-[(12S,14S,16R)-16-(1,1-difluoroethyl)-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8-tetraen-12-yl]-12-ethyl-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: 162652-95-1
• 化学式: C₄₅H₅₄F₂N₄O₈
• 分子量: 816.943
• InChiKey: NMDYYWFGPIMTKO-KLCPSUAYSA-N

物化性质

• 密度：
  1.39±0.1 g/cm3(Predicted)
• 熔点：
  244

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  59
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  13

ADMET

代谢

流感病毒的代谢物主要是细胞色素P450 3A4，但4-O-脱乙酰基流感病毒（DVFL）可能由多种酯酶缓慢形成。DVFL是主要的代谢物，并且是唯一保留药理活性的代谢物。

The metabolites of influnine are mostly cytochrome P450 3A4, but 4-O-deacetylvinflunine (DVFL) may be slowly formed by multiple esterases. DVFL is the main metabolite and is the only metabolite that retains pharmacological activity.

来源:DrugBank

毒理性

• 蛋白质结合

Vinflunine is 67.2 ± 1.1% bound to human plasma proteins. It mainly binds to high density lipoproteins and serum albumin, and is non-saturable on the range of vinflunine concentrations observed in patients. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%).

Vinflunine is 67.2 ± 1.1% bound to human plasma proteins. It mainly binds to high density lipoproteins and serum albumin, and is non-saturable on the range of vinflunine concentrations observed in patients.. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%).

来源:DrugBank

吸收、分配和排泄

• 吸收

Vinflunine在癌症患者中表现出线性药代动力学特性，给药剂量范围从30 mg/m^2到400 mg/m^2。

Vinflunine displays a linear pharmacokinetic profile in the range of administered doses (from 30 mg/m^2 to 400 mg/m^2) in cancer patients.

来源:DrugBank

吸收、分配和排泄

• 消除途径

粪便排泄占长春瑞滨及其代谢物总消除的2/3，其余1/3通过尿液排泄。

Fecal excretion accounts for 2/3 of the total elimination of vinflunine and its metabolites and the remaining 1/3 of their elimination indicates urinary excretion.

来源:DrugBank

吸收、分配和排泄

• 分布容积

终末分布容积很大，2422 ± 676 L（约35 l/kg），表明广泛分布到组织中。血浆与全血浓度之比为0.80 ± 0.12。

The terminal volume of distribution is large, 2422 ± 676 L (about 35 l/kg), suggesting extensive distribution into tissues. The ratio between plasma and whole blood concentrations of 0.80 ± 0.12.

来源:DrugBank

吸收、分配和排泄

• 清除

总血液清除率为40升/小时，这是根据对372名患者进行的人群药代动力学分析得出的。个体间和个体内的变异性较低，变异系数分别大约为25%和8%。

The total blood clearance was 40 L/h according to a population pharmacokinetic analysis in 372 patients. The inter- and intra-individual variability was low, with the coefficient of variation approximately 25% and 8%, respectively.

来源:DrugBank

制备方法与用途

膀胱癌治疗药物——长春氟宁是一种新型的长春化碱化合物，由长春瑞宾衍生而来。通过Superacidic chemistry技术，在母体化合物上引入了两个氟原子。该化合物能够与微管相互作用，抑制微管聚合，使细胞在有丝分裂中期停止。其微管结合活性与其他长春花碱化合物相比有所不同，显示出更强的抗肿瘤作用。目前，临床应用已将其用于膀胱癌治疗。

反应信息

• 作为反应物：
  描述：

  长春氟宁 在 N-碘代丁二酰亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以94%的产率得到
  参考文献：
  名称：

  Synthesis and biological evaluation of C-12′ substituted vinflunine derivatives

  摘要：

  A series of novel C-12' substituted vinflunine derivatives have been synthesized. Several compounds in this series possess comparable in vitro cytotoxic potency against A549 cell lines. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.07.025
• 作为产物：
  描述：

  长春瑞宾 在 氢氟酸 、 氯化锑(V) 作用下， 以 四氯化碳 为溶剂， 以35%的产率得到长春氟宁
  参考文献：
  名称：

  Regio-selective chlorination of vinca alkaloids catalyzed by Lewis acid

  摘要：

  一种新型的C-17-氯代替苯瑞林或长春氟宁衍生物，通过路易斯酸催化下的氯化反应，实现了区域选择性合成。催化剂Cp2TiCl2在氯化反应中发挥了关键作用。

  DOI：

  10.1007/s11426-011-4310-2

文献信息

• VINBLASTINE DERIVATIVES, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
  申请人：JINAN UNIVERSITY

  公开号：US20160068552A1

  公开（公告）日：2016-03-10

  The present invention provides a new kind of vinca alkaloid derivatives, new applications thereof and preparation methods therefor. The vinca alkaloid derivatives comprise hydrazinolyzed vinca alkaloids and vinca alkaloid dipeptide derivative. The hydrazinolyzed vinca alkaloids are the compounds obtained from the reaction of vinca alkaloids or salts thereof with hydrazinolyzed hydrate; and the vinca alkaloid dipeptide derivatives are the compounds obtained from the condensation of hydrazinolyzed vinca alkaloids with N-benzyloxycarbonylglycyl proline. The present invention provides the uses of the vinca alkaloids derivatives or the pharmaceutical compositions thereof in anti-tumor, preventing or treating diabetic retinopathy, rheumatoid arthritis and serving as angiogenesis inhibitors or vascular disrupting agents.

  本发明提供了一种新型的长春碱衍生物，以及其新的应用和制备方法。长春碱衍生物包括水解长春碱和长春碱二肽衍生物。水解长春碱是通过长春碱或其盐与水解水合物反应得到的化合物；而长春碱二肽衍生物是通过水解长春碱与N-苄氧羰基甘氨酸脯氨酸的缩合反应得到的化合物。本发明提供了长春碱衍生物或其药物组合物在抗肿瘤、预防或治疗糖尿病视网膜病变、类风湿性关节炎以及作为血管生成抑制剂或血管破坏剂中的用途。
• WO2008/98970
  申请人：——

  公开号：——

  公开（公告）日：——
• <i>Vinca</i> Alkaloids in Superacidic Media:  A Method for Creating a New Family of Antitumor Derivatives
  作者：Jacques Fahy、Alain Duflos、Jean-Paul Ribet、Jean-Claude Jacquesy、Christian Berrier、Marie-Paule Jouannetaud、Fabien Zunino

  DOI：10.1021/ja971864w

  日期：1997.9.1
• Folate–Vinca Alkaloid Conjugates for Cancer Therapy: A Structure–Activity Relationship
  作者：Christopher P. Leamon、Iontcho R. Vlahov、Joseph A. Reddy、Marilynn Vetzel、Hari Krishna R. Santhapuram、Fei You、Alicia Bloomfield、Ryan Dorton、Melissa Nelson、Paul Kleindl、Jeremy F. Vaughn、Elaine Westrick

  DOI：10.1021/bc400441s

  日期：2014.3.19

  Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.
• Synthesis and biological evaluation of C-12′ substituted vinflunine derivatives
  作者：Lei Xin Sheng、Yu Xiang Da、Yin Long、Liu Zhen Hong、Tang Peng Cho

  DOI：10.1016/j.bmcl.2008.07.025

  日期：2008.8

  A series of novel C-12' substituted vinflunine derivatives have been synthesized. Several compounds in this series possess comparable in vitro cytotoxic potency against A549 cell lines. (C) 2008 Elsevier Ltd. All rights reserved.