N-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-4-oxo- 2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-4-oxo- 2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide
• 英文别名: N-[2-methoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-3-methyl-4-oxo-5,6,7,8-tetrahydro-2H-cyclohepta[c]pyrrole-1-carboxamide
• 化学式: C₂₃H₃₀N₄O₅S
• 分子量: 474.581
• InChiKey: AFNYOROEWXANDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-甲氧基-3-硝基苯磺酰氯 在 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 5%-palladium/activated carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 52.0h， 生成 N-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-4-oxo- 2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide
  参考文献：
  名称：

  4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines

  摘要：

  Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI₅₀ determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.

  DOI：

  10.1021/acs.jmedchem.0c00478

文献信息

• [EN] CONDENSED PYRROLES AS NOVEL BROMODOMAIN INHIBITORS<br/>[FR] PYRROLES CONDENSÉS UTILISÉS EN TANT QUE NOUVEAUX INHIBITEURS DE BROMODOMAINES
  申请人：ALBERT LUDWIG UNIV FREIBURG

  公开号：WO2020127846A9

  公开（公告）日：2021-08-12
• CONDENSED PYRROLES AS NOVEL BROMODOMAIN INHIBITORS
  申请人：Albert-Ludwigs-Universität Freiburg

  公开号：EP3898587A1

  公开（公告）日：2021-10-27
• 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines
  作者：Martin Hügle、Pierre Regenass、Robin Warstat、Mirjam Hau、Karin Schmidtkunz、Xavier Lucas、Daniel Wohlwend、Oliver Einsle、Manfred Jung、Bernhard Breit、Stefan Günther

  DOI：10.1021/acs.jmedchem.0c00478

  日期：2020.12.24

  Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI₅₀ determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.