| 1301177-26-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• CAS: 1301177-26-3
• 化学式: C₂₀H₁₉BrN₂O₂
• 分子量: 399.287
• InChiKey: IBNHSSKZPICMPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.32
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  62.86
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  在 三乙酰氧基硼氢化钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 生成 4-(2-(2-((3-amino-2-methylpropyl)amino)ethyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-bromobenzonitrile
  参考文献：
  名称：

  Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

  摘要：

  A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.02.101
• 作为产物：
  描述：

  2-bromo-4-(2-(2,3-dihydroxypropyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile 在 sodium periodate 、 silica gel 作用下， 以 二氯甲烷 为溶剂， 以100%的产率得到
  参考文献：
  名称：

  Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity

  摘要：

  A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.03.112

文献信息

• Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model
  作者：Christoph W. Zapf、Jonathan D. Bloom、Jamie L. McBean、Russell G. Dushin、Jennifer M. Golas、Hao Liu、Judy Lucas、Frank Boschelli、Erik Vogan、Jeremy I. Levin

  DOI：10.1016/j.bmcl.2011.04.102

  日期：2011.6

  A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth. (C) 2011 Elsevier Ltd. All rights reserved.
• Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model
  作者：Christoph W. Zapf、Jonathan D. Bloom、Zhong Li、Russell G. Dushin、Thomas Nittoli、Mercy Otteng、Antonia Nikitenko、Jennifer M. Golas、Hao Liu、Judy Lucas、Frank Boschelli、Erik Vogan、Andrea Olland、Mark Johnson、Jeremy I. Levin

  DOI：10.1016/j.bmcl.2011.05.102

  日期：2011.8

  An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction. (C) 2011 Elsevier Ltd. All rights reserved.