4-((1S,9S,9aS,11R,11bR)-11-acetoxy-1-(methoxymethyl)-9a,11b-dimethyl-3,6-dioxo-3,6,6b,7,8,9,9a,10,11,11b-decahydro-1H-furo[4,3,2-de]indeno[4,5-h]isochromen-9-yloxy)-6-oxohexanoic acid | 1067880-63-0

• 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-((1S,9S,9aS,11R,11bR)-11-acetoxy-1-(methoxymethyl)-9a,11b-dimethyl-3,6-dioxo-3,6,6b,7,8,9,9a,10,11,11b-decahydro-1H-furo[4,3,2-de]indeno[4,5-h]isochromen-9-yloxy)-6-oxohexanoic acid
• 英文别名: 6-[[(1R,3R,5S,6S,9R,18S)-3-acetyloxy-18-(methoxymethyl)-1,5-dimethyl-11,16-dioxo-13,17-dioxapentacyclo[10.6.1.02,10.05,9.015,19]nonadeca-2(10),12(19),14-trien-6-yl]oxy]-6-oxohexanoic acid
• CAS: 1067880-63-0
• 化学式: C₂₉H₃₄O₁₁
• 分子量: 558.582
• InChiKey: BBZBEPZXQDPYQJ-UOSLBTIISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  156
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  31-(trimethylsilylether)rapamycin 、 4-((1S,9S,9aS,11R,11bR)-11-acetoxy-1-(methoxymethyl)-9a,11b-dimethyl-3,6-dioxo-3,6,6b,7,8,9,9a,10,11,11b-decahydro-1H-furo[4,3,2-de]indeno[4,5-h]isochromen-9-yloxy)-6-oxohexanoic acid 在 4-二甲氨基吡啶 、 N,N'-二异丙基碳二亚胺 作用下， 以 1,2-二氯乙烷 为溶剂， 生成
  参考文献：
  名称：

  Hybrid Inhibitors of Phosphatidylinositol 3-Kinase (PI3K) and the Mammalian Target of Rapamycin (mTOR): Design, Synthesis, and Superior Antitumor Activity of Novel Wortmannin−Rapamycin Conjugates

  摘要：

  Hyperactivation of the P13K/AKT/mTOR signaling pathway is common in cancer, and P13K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of P13K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortinannin (2a) analogues conjugated to rapamycin (3a) analogues viaa prodrug linker are uniquely positioned for this approach. Out- efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacyover3aor9a whenadministered asa singleagentorincombination with bevacizumab. Thus, We have uncovered it novel approach to target both P13K and mTOR via hybrid inhibitors, leading to it broader and more robust anticanccr efficacy.

  DOI：

  10.1021/jm901427g
• 作为产物：
  描述：

  17β-羟基渥曼青霉素 、 己二酸酐 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 乙腈 为溶剂， 以835 mg的产率得到4-((1S,9S,9aS,11R,11bR)-11-acetoxy-1-(methoxymethyl)-9a,11b-dimethyl-3,6-dioxo-3,6,6b,7,8,9,9a,10,11,11b-decahydro-1H-furo[4,3,2-de]indeno[4,5-h]isochromen-9-yloxy)-6-oxohexanoic acid
  参考文献：
  名称：

  Hybrid Inhibitors of Phosphatidylinositol 3-Kinase (PI3K) and the Mammalian Target of Rapamycin (mTOR): Design, Synthesis, and Superior Antitumor Activity of Novel Wortmannin−Rapamycin Conjugates

  摘要：

  Hyperactivation of the P13K/AKT/mTOR signaling pathway is common in cancer, and P13K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of P13K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortinannin (2a) analogues conjugated to rapamycin (3a) analogues viaa prodrug linker are uniquely positioned for this approach. Out- efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacyover3aor9a whenadministered asa singleagentorincombination with bevacizumab. Thus, We have uncovered it novel approach to target both P13K and mTOR via hybrid inhibitors, leading to it broader and more robust anticanccr efficacy.

  DOI：

  10.1021/jm901427g