(3-methyloxetan-3-yl)methyl 8-bromooctanoate | 1208238-85-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (3-methyloxetan-3-yl)methyl 8-bromooctanoate
• CAS: 1208238-85-0
• 化学式: C₁₃H₂₃BrO₃
• 分子量: 307.228
• InChiKey: KVIIKKYUSVZXNU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  17.0
• 可旋转键数：
  9.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  35.53
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (3-methyloxetan-3-yl)methyl 8-bromooctanoate 在 锂硼氢 、 三氟化硼乙醚 、 4-甲基苯磺酸吡啶 、 caesium carbonate 、 sodium sulfate 、 sodium iodide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 二氯甲烷 、 丙酮 为溶剂， 反应 61.0h， 生成 16α-(7-carboxyheptyl)-16β-hydroxymethyl-1,3,5(10)-estratrien-3,17-diol
  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：

  3-甲基-3-羟甲基氧杂环丁烷 、 8-溴辛酰氯 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (3-methyloxetan-3-yl)methyl 8-bromooctanoate
  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

文献信息

• Multi-arm polymeric alkanoate conjugates
  申请人：NEKTAR THERAPEUTICS

  公开号：US09220790B2

  公开（公告）日：2015-12-29

  Among other aspects, provided herein are multi-armed polymer conjugates comprising an alkanoate-linker, compositions comprising such conjugates, and related methods of making and administering the same. Methods of treatment employing such conjugates and related uses are also provided. The conjugates are prepared with high drug loading efficiencies.

  本文提供了包含烷酸酯连接剂的多臂聚合物共轭物，包含这种共轭物的组合物，以及制备和给药这些共轭物的相关方法。还提供了使用这种共轭物进行治疗的方法和相关用途。这些共轭物具有高药物装载效率。
• Lessons in Strain and Stability: Enantioselective Synthesis of (+)‐[5]‐Ladderanoic Acid
  作者：Erin N. Hancock、Erin L. Kuker、Dean J. Tantillo、M. Kevin Brown

  DOI：10.1002/anie.201910901

  日期：2020.1.2

  The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)-[5]-ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic

  结构复杂且高度紧张的天然产物的合成为新反应和策略的开发提供了独特的挑战和意想不到的机会。在此，报道了(+)-[5]-梯烷酸的合成。在到达目标的途中，发现了不寻常和意想不到的应变释放驱动的转化。这一事件需要对合成设计进行彻底修改，最终导致通过烯丙基硼化/Zweifel 烯化序列开发出新型逐步环丁烷组装。