N-(3-(dimethylamino)propyl)-1-methyl-4-(1-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxamide | 1428305-94-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: N-(3-(dimethylamino)propyl)-1-methyl-4-(1-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxamide
• 英文别名: N-[5-[3-(dimethylamino)propylcarbamoyl]-1-methylpyrrol-3-yl]-1-methyl-4-(4-nitrophenyl)pyrrole-2-carboxamide
• CAS: 1428305-94-5
• 化学式: C₂₃H₂₈N₆O₄
• 分子量: 452.513
• InChiKey: TZMBGMZJHMUNRH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(3-(dimethylamino)propyl)-1-methyl-4-(1-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxamide 在 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 乙酸乙酯 为溶剂， 反应 4.5h， 生成 N-(4-(5-((5-((3-(dimethylamino)propyl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamide
  参考文献：
  名称：

  GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

  摘要：

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.

  DOI：

  10.1021/jm301882a
• 作为产物：
  描述：

  2,2,2-三氯-1-(1-甲基-1H-吡咯-2-基)-乙酮 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 氢气 、 硝酸 、 乙酸酐 、 potassium carbonate 、 1-羟基苯并三唑 、 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 甲苯 为溶剂， -5.0~100.0 ℃ 、310.27 kPa 条件下， 反应 20.0h， 生成 N-(3-(dimethylamino)propyl)-1-methyl-4-(1-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

  摘要：

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.

  DOI：

  10.1021/jm301882a

文献信息

• GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models
  作者：Khondaker M. Rahman、Paul J. M. Jackson、Colin H. James、B. Piku Basu、John A. Hartley、Maria de la Fuente、Andreas Schatzlein、Mathew Robson、R. Barbara Pedley、Chris Pepper、Keith R. Fox、Philip W. Howard、David E. Thurston

  DOI：10.1021/jm301882a

  日期：2013.4.11

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.