10'-fluorovinblastine | 1328885-59-1

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 英文名称: 10'-fluorovinblastine
• 英文别名: methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15R,17S)-17-ethyl-7-fluoro-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5(10),6,8-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: 1328885-59-1
• 化学式: C₄₆H₅₇FN₄O₉
• 分子量: 828.978
• InChiKey: JQDGXTXFHANTTF-FXDREALHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  60
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  154
• 氢给体数：
  3
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  10'-fluorovinblastine 、 5,6,7,8-四羟基-2-萘甲酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成
  参考文献：
  名称：

  Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance

  摘要：

  A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

  DOI：

  10.1021/acs.jmedchem.7b00958
• 作为产物：
  描述：

  10-nitrocatharanthine 在 盐酸 、 sodium tetrahydroborate 、 tetrafluoroboric acid 、 ferric(III)oxalate hexahydrate 、 2,2,2-三氟乙醇 、 iron(III) chloride hexahydrate 、 氢气 作用下， 以 甲醇 、 水 、 丙酮 、 乙腈 为溶剂， 反应 11.75h， 生成 10'-fluorovinblastine
  参考文献：
  名称：

  10′-Fluorovinblastine and 10′-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids

  摘要：

  A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10'-fluorovinblastine and 10'-fluorovincristine. In addition to defining a pronounced and la unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10', which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC50 = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC50 = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting that the 10'-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions.

  DOI：

  10.1021/ml200236a

文献信息

• [EN] 10'-FLUORINATED VINCA ALKALOIDS PROVIDE ENHANCED BIOLOGICAL ACTIVITY AGAINST MDR CANCER CELLS<br/>[FR] VINCA-ALCALOÏDES 10'-FLUORÉS DOTÉS D'UNE ACTIVITÉ BIOLOGIQUE AUGMENTÉE CONTRE LES CELLULES CANCÉREUSES MULTIRÉSISTANTES
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2011103007A3

  公开（公告）日：2012-01-05