tert-butyl (1S)-2-[(5-bromo-2-chloropyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylcarbamate | 552330-37-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: tert-butyl (1S)-2-[(5-bromo-2-chloropyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylcarbamate
• 英文别名: tert-butyl N-[(2S)-1-(5-bromo-2-chloropyridin-3-yl)oxy-3-(1H-indol-3-yl)propan-2-yl]carbamate
• CAS: 552330-37-7
• 化学式: C₂₁H₂₃BrClN₃O₃
• 分子量: 480.789
• InChiKey: CLFJZXIUOXSMGH-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  76.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (1S)-2-[(5-bromo-2-chloropyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylcarbamate 在 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1S)-2-[(2-chloro-5-isoquinolin-6-ylpyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylamine
  参考文献：
  名称：

  Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity

  摘要：

  The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t(1/2) = 0.3 h, po F= 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t(1/2) = 5.0 h, po F = 51%) but resulted in > 500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.03.041
• 作为产物：
  描述：

  3-苯甲氧基-5-溴吡啶 在 氢溴酸 、 溶剂黄146 、 间氯过氧苯甲酸 、 三苯基膦 、 偶氮二甲酸二乙酯 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 tert-butyl (1S)-2-[(5-bromo-2-chloropyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylcarbamate
  参考文献：
  名称：

  Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity

  摘要：

  The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t(1/2) = 0.3 h, po F= 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t(1/2) = 5.0 h, po F = 51%) but resulted in > 500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.03.041

文献信息

• Discovery of trans-3,4′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation
  作者：Qun Li、Tongmei Li、Gui-Dong Zhu、Jianchun Gong、Akiyo Claibone、Chris Dalton、Yan Luo、Eric F. Johnson、Yan Shi、Xuesong Liu、Vered Klinghofer、Joy L. Bauch、Kennan C. Marsh、Jennifer J. Bouska、Shannon Arries、Ron De Jong、Tilman Oltersdorf、Vincent S. Stoll、Clarissa G. Jakob、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1016/j.bmcl.2005.12.017

  日期：2006.3

  A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC50 values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined. (C) 2005 Elsevier Ltd. All rights reserved.