16β-methoxycarbonyl-16α-(3-[4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl]propyl)-3-(tetrahydropyrannyloxy)-1,3,5(10)-estratrien-17-one | 1399155-90-8

• 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: 16β-methoxycarbonyl-16α-(3-[4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl]propyl)-3-(tetrahydropyrannyloxy)-1,3,5(10)-estratrien-17-one
• CAS: 1399155-90-8
• 化学式: C₃₄H₄₆O₈
• 分子量: 582.734
• InChiKey: GBBYFDAJPITGSG-OTHPQITESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.69
• 重原子数：
  42.0
• 可旋转键数：
  7.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  89.52
• 氢给体数：
  0.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  16β-methoxycarbonyl-16α-(3-[4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl]propyl)-3-(tetrahydropyrannyloxy)-1,3,5(10)-estratrien-17-one 在 锂硼氢 、 4-甲基苯磺酸吡啶 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 70.5h， 生成 16β-hydroxymethyl-1,3,5(10)-estratrien-3,17-diol-16α-butanoic acid N-doxorubicinamide
  参考文献：
  名称：

  Design, synthesis, cytocidal activity and estrogen receptor α affinity of doxorubicin conjugates at 16α-position of estrogen for site-specific treatment of estrogen receptor positive breast cancer

  摘要：

  Doxorubicin (DOX) is an important medicine for the treatment of breast cancer, which is the most frequently diagnosed and the most lethal cancer in women worldwide. However, the clinical use of DOX is impeded by serious toxic effects such as cardiomyopathy and congestive heart failure. Covalently linking DOX to estrogen to selectively deliver the drug to estrogen receptor-positive (Er) cancer tissues is one of the strategies under investigation for improving the efficacy and decreasing the cardiac toxicity of DOX. However, conjugation of drug performed until now was at 3- or 17-position of estrogen, which is not ideal since the hydroxyl groups at this position are important for receptor binding affinity. In this study, we designed, prepared and evaluated in vitro the first estrogen-doxorubicin conjugates at 16 alpha-position of estradiol termed E-DOXs (8a-d). DOX was conjugated using a 3-9 carbon atoms alkylamide linking arm. E-DOXs were prepared from estrone using a seven-step procedure to afford the desired conjugates in low to moderate yields. The antiproliferative activities of the E-DOX 8a conjugate through a 3-carbon spacer chain on ER+ MCF7 and HT-29 are in the micromolar range while inactive on M21 and the ER- MDA-MB-231 cells (>50 mu M). Compound 8a exhibits a selectivity ratio (ER+/ER- cell lines) of >3.5. Compounds 8b-8d bearing alkylamide linking arms ranging from 5 to 9 carbon atoms were inactive at the concentrations tested (>50 mu M). Interestingly, compounds 8a-8c exhibited affinity for the estrogen receptor alpha (ER alpha) in the nanomolar range (72-100 nM) whereas compound 8d exhibited no affinity at concentrations up to 215 nM. These results indicate that a short alkylamide spacer is required to maintain both antiproliferative activity toward ER+ MCF7 and affinity for the ER alpha of the E-DOX conjugates. Compound 8a is potentially a promising conjugate to target ER. breast cancer and might be useful also for the design of more potent E-DOX conjugates. (C) 2012 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2012.06.004
• 作为产物：
  描述：

  雌酚酮 在 4-甲基苯磺酸吡啶 、 potassium hydride 、 caesium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 28.5h， 生成 16β-methoxycarbonyl-16α-(3-[4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl]propyl)-3-(tetrahydropyrannyloxy)-1,3,5(10)-estratrien-17-one
  参考文献：
  名称：

  Design, synthesis, cytocidal activity and estrogen receptor α affinity of doxorubicin conjugates at 16α-position of estrogen for site-specific treatment of estrogen receptor positive breast cancer

  摘要：

  Doxorubicin (DOX) is an important medicine for the treatment of breast cancer, which is the most frequently diagnosed and the most lethal cancer in women worldwide. However, the clinical use of DOX is impeded by serious toxic effects such as cardiomyopathy and congestive heart failure. Covalently linking DOX to estrogen to selectively deliver the drug to estrogen receptor-positive (Er) cancer tissues is one of the strategies under investigation for improving the efficacy and decreasing the cardiac toxicity of DOX. However, conjugation of drug performed until now was at 3- or 17-position of estrogen, which is not ideal since the hydroxyl groups at this position are important for receptor binding affinity. In this study, we designed, prepared and evaluated in vitro the first estrogen-doxorubicin conjugates at 16 alpha-position of estradiol termed E-DOXs (8a-d). DOX was conjugated using a 3-9 carbon atoms alkylamide linking arm. E-DOXs were prepared from estrone using a seven-step procedure to afford the desired conjugates in low to moderate yields. The antiproliferative activities of the E-DOX 8a conjugate through a 3-carbon spacer chain on ER+ MCF7 and HT-29 are in the micromolar range while inactive on M21 and the ER- MDA-MB-231 cells (>50 mu M). Compound 8a exhibits a selectivity ratio (ER+/ER- cell lines) of >3.5. Compounds 8b-8d bearing alkylamide linking arms ranging from 5 to 9 carbon atoms were inactive at the concentrations tested (>50 mu M). Interestingly, compounds 8a-8c exhibited affinity for the estrogen receptor alpha (ER alpha) in the nanomolar range (72-100 nM) whereas compound 8d exhibited no affinity at concentrations up to 215 nM. These results indicate that a short alkylamide spacer is required to maintain both antiproliferative activity toward ER+ MCF7 and affinity for the ER alpha of the E-DOX conjugates. Compound 8a is potentially a promising conjugate to target ER. breast cancer and might be useful also for the design of more potent E-DOX conjugates. (C) 2012 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2012.06.004