(10S,13S)-9-Allyl-13-hydroxymethyl-10-isopropyl-3,9,12-triaza-tricyclo[6.6.1.0^4,15]pentadeca-1,4,6,8(15)-tetraen-11-one | 163084-14-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (10S,13S)-9-Allyl-13-hydroxymethyl-10-isopropyl-3,9,12-triaza-tricyclo[6.6.1.0^4,15]pentadeca-1,4,6,8(15)-tetraen-11-one
• 英文别名: (10S,13S)-13-(hydroxymethyl)-10-propan-2-yl-9-prop-2-enyl-3,9,12-triazatricyclo[6.6.1.04,15]pentadeca-1,4(15),5,7-tetraen-11-one
• CAS: 163084-14-8
• 化学式: C₁₉H₂₅N₃O₂
• 分子量: 327.426
• InChiKey: UGPWXVQFDNRUHL-KSSFIOAISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  68.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (10S,13S)-9-Allyl-13-hydroxymethyl-10-isopropyl-3,9,12-triaza-tricyclo[6.6.1.0^4,15]pentadeca-1,4,6,8(15)-tetraen-11-one 在 吡啶 、 sodium hydroxide 、 三氯化铝 、 sodium acetate 、 溶剂黄146 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 1,4-二氧六环 、 xylene 为溶剂， 反应 4.83h， 生成 (12S,15S)-12-(hydroxymethyl)-2-methyl-6-(3-methylbut-2-enyl)-15-propan-2-yl-1,8,13-triazatetracyclo[8.5.2.04,16.07,17]heptadeca-2,4,6,9,16-pentaen-14-one
  参考文献：
  名称：

  Synthesis and Biological Activities of New Conformationally Restricted Analogues of (−)-Indolactam-V:  Elucidation of the Biologically Active Conformation of the Tumor-Promoting Teleocidins

  摘要：

  The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative, Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

  DOI：

  10.1021/ja961727j
• 作为产物：
  描述：

  (-)-N¹³-desmethylindolactam V 、 3-溴丙烯 在 碳酸氢钠 作用下， 以 甲醇 为溶剂， 反应 19.0h， 以35%的产率得到(10S,13S)-9-Allyl-13-hydroxymethyl-10-isopropyl-3,9,12-triaza-tricyclo[6.6.1.0^4,15]pentadeca-1,4,6,8(15)-tetraen-11-one
  参考文献：
  名称：

  Synthesis and Biological Activities of New Conformationally Restricted Analogues of (−)-Indolactam-V:  Elucidation of the Biologically Active Conformation of the Tumor-Promoting Teleocidins

  摘要：

  The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative, Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

  DOI：

  10.1021/ja961727j

文献信息

• Synthesis and Biological Activities of New Conformationally Restricted Analogues of (−)-Indolactam-V:  Elucidation of the Biologically Active Conformation of the Tumor-Promoting Teleocidins
  作者：Kazuhiro Irie、Tomomi Isaka、Yoriko Iwata、Yoshiaki Yanai、Yoshimasa Nakamura、Fumito Koizumi、Hajime Ohigashi、Paul A. Wender、Yoshiko Satomi、Hoyoku Nishino

  DOI：10.1021/ja961727j

  日期：1996.1.1

  The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative, Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.