42,17'-linked rapamycin-adipate-wortmannin conjugate | 1067892-20-9

• 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: 42,17'-linked rapamycin-adipate-wortmannin conjugate
• 英文别名: 6-O-[(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] 1-O-[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] hexanedioate
• CAS: 1067892-20-9
• 化学式: C₈₀H₁₁₁NO₂₃
• 分子量: 1454.75
• InChiKey: FZKUVAULFUQOEH-FFYJISJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9
• 重原子数：
  104
• 可旋转键数：
  19
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  320
• 氢给体数：
  2
• 氢受体数：
  23

反应信息

• 作为反应物：
  描述：

  42,17'-linked rapamycin-adipate-wortmannin conjugate 、 三甲基-1,3-丙二胺 以 甲基叔丁基醚 为溶剂， 以65%的产率得到(1E,4S,4aR,5R,6aS,7S)-5-(acetyloxy)-1-{[[3-(dimethylamino)-propyl](methyl)amino]methylene}-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-7-yl-(1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl hexanedioate
  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：

  在 硫酸 、 水 作用下， 以 乙腈 为溶剂， 生成 42,17'-linked rapamycin-adipate-wortmannin conjugate
  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

文献信息

• WORTMANNIN-RAPAMYCIN CONJUGATE AND USES THEREOF
  申请人：GU JIANXIN

  公开号：US20080249123A1

  公开（公告）日：2008-10-09

  A rapamycin—wortmannin conjugate is described, in which the conjugate is formed by linking the rapamycin and wortmannin together in such a manner that the rapamycin and the wortmannin are separated following administration to a subject. Use of such a conjugate in an antineoplastic regimen is described.

  描述了一种雷帕霉素-沃特曼宾共轭物，其中共轭物通过将雷帕霉素和沃特曼宾连接在一起形成，以便在给予受试者后分离雷帕霉素和沃特曼宾。描述了在抗肿瘤方案中使用这种共轭物的方法。