4-Fluoro-11beta-methoxy-ethinylestradiol | 151160-27-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 4-Fluoro-11beta-methoxy-ethinylestradiol
• 英文别名: (8S,9S,11S,13S,14S,17R)-17-ethynyl-4-fluoro-11-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
• CAS: 151160-27-9
• 化学式: C₂₁H₂₅FO₃
• 分子量: 344.426
• InChiKey: VMXVMTLLLCLNKI-NIOPCZSGSA-N

物化性质

• 沸点：
  461.3±45.0 °C(predicted)
• 密度：
  1.26±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  49.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-Fluoro-11beta-methoxy-ethinylestradiol 、 [1-[(3,5-二甲基-1H-吡咯-2-基)(3,5-二甲基-2H-吡咯-2-亚基)甲基]-4-碘苯](二氟硼烷) 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 6.5h， 以53%的产率得到4-flouro-11β-methoxy-17α-[-(4-ethynylphenyl)-(4,4-difluoro-8-(1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene))]3,17β-estradiol
  参考文献：
  名称：

  BODIPY-17α-乙炔基雌二醇共轭物：合成，荧光性质和受体结合亲和力

  摘要：

  体内乳腺癌中雌激素受体（ER）密度的成像是分期疾病，指导治疗方案和治疗结果随访的潜在工具。正电子发射断层扫描（PET）和荧光成像都已受到足够的重视，以检测配体-ER相互作用。在这项研究中，我们使用4,4-二氟-4-硼3a，4a-二氮杂-s-茚并四烯（BODIPY）作为荧光探针和雌二醇衍生物作为配体制备了BODIPY-雌二醇共轭物，并建立了它们的相对结合亲和力（RBA） ERα。缀合物的合成涉及使用Sonogashira将BODIPY部分连接到雌二醇的C17α位置，或使碘代-BODIPY或aza-BODIPY与各种17α-乙炔基雌二醇（EE2）衍生物发生点击反应。用EE2-BODIPY共轭物观察到ERα的最高RBA（7）具有线性的八碳间隔基链。正在进行ER阳性小鼠肿瘤模型中的细胞摄取研究和体内成像实验。

  DOI：

  10.1016/j.bmcl.2016.12.052
• 作为产物：
  描述：

  11β-methoxyestrone 在 三氟甲磺酸N-吡啶鎓 作用下， 以 1,1,2-三氯乙烷 、 二甲基亚砜 为溶剂， 反应 20.0h， 生成 4-Fluoro-11beta-methoxy-ethinylestradiol
  参考文献：
  名称：

  Synthesis of A-ring fluorinated derivatives of iodine-125-labeled (17.alpha.,20E/Z)-iodovinylestradiols: effect on receptor binding and receptor-mediated target tissue uptake

  摘要：

  We have prepared a series of 2- and 4-fluoro derivatives of the isomeric (17alpha,20E)- and (17alpha,20Z)iodovinylestradiols (IVE2) and also the analogs substituted with either a 7alpha-methyl (7alpha-Me-IVE2) or 11beta-methoxy group (11beta-OMe-IVE2) and evaluated their in vitro and in vivo properties. Electrophilic substitution of the estrone derivatives with N-fluoropyridinium salt gave the 2- and 4-fluoro analogs which were subsequently converted to the 17alpha-ethynyl derivatives. The tributylstannyl intermediates were obtained from the corresponding 17alpha-ethynyl analogs using azobisisobutyronitrile or triethylborane as catalyst. All 12 products were also prepared as their no-carrier-added [I-125]iodovinyl analogs via destannylation of the tributylstannyl precursors. Binding affinity for the estrogen receptor (ER) was in general higher for the 4-F derivatives as compared to the 2-F derivatives, while the 20Z isomers of the same compounds showed somewhat higher ER binding affinity as compared to the 20E isomers. The combination of an A-ring fluoro and 7alpha- or 11beta-substituent decreased ER binding affinity. Substitution of a fluoro atom at C-4 on either the 17alpha-ethynylestradiol or isomeric 17alpha-IVE2 enhanced the affinity of the parent molecule for the ER. A-ring fluorination of all other analogues tested had no effect or depressed ER binding affinity. Varying incubation conditions showed substantial differences in ER binding kinetics between the 20E and 20Z isomers. Tissue distribution in immature female rats showed that the highest uterus uptake and uterus to blood/nontarget ratios in the IVE2 series were obtained with the 4-F-(17alpha,20Z)IVE2 isomer. The combination of A-ring fluoro and 7alpha- or 11beta-substitution decreased uterus uptake but had little or no effect on uterus to blood/nontarget ratios. The highest uterus to blood ratios were observed for the 4-F-(17alpha,20E)11beta-OMe-IVE2 (75 at 6 h and 125 at 12 h pi) reflecting rapid blood clearance and in vivo stability, as confirmed by the low levels of thyroid radioactivity. The lack of correlation between ER binding affinities and uterus uptake, and/or uptake ratios, suggests that other factors, including nonspecific binding and metabolic processes, also are involved in the tissue localization process. Our data suggest that 4-F substitution onto (17alpha,20Z)IVE2 and (17alpha,20E)11beta-OMe-IVE2 enhances the potential of these compounds to function as SPECT imaging agents of ER-rich tissues.

  DOI：

  10.1021/jm00073a004