(7R,8R,9S,13S,14S,17R)-17-ethynyl-4-fluoro-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | 151160-26-8

• 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: (7R,8R,9S,13S,14S,17R)-17-ethynyl-4-fluoro-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
• CAS: 151160-26-8
• 化学式: C₂₁H₂₅FO₂
• 分子量: 328.427
• InChiKey: CUSUNOCLNDQSQL-ZWZSLVANSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (7R,8R,9S,13S,14S,17R)-17-ethynyl-4-fluoro-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol 在 三乙基硼 、 碘 、 三正丁基氢锡 作用下， 生成 (7R,8R,9S,13S,14S,17R)-4-Fluoro-17-((Z)-2-iodo-vinyl)-7,13-dimethyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol 、 (7R,8R,9S,13S,14S,17R)-4-Fluoro-17-((E)-2-iodo-vinyl)-7,13-dimethyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
  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
• 作为产物：
  描述：

  阿美雌酮 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 (7R,8R,9S,13S,14S,17R)-17-ethynyl-4-fluoro-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
  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

文献信息

• 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
  作者：Hasrat Ali、Jacques Rousseau、Johan E. van Lier

  DOI：10.1021/jm00073a004

  日期：1993.10

  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.