(S)-methyl 4-(4-(4-(4-(4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)butanamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate | 1383714-45-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (S)-methyl 4-(4-(4-(4-(4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)butanamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate
• 英文别名: (S)-methyl 4-(4-(4-(4-(4-(7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate；methyl 4-[[4-[[4-[4-[4-[[(6aS)-2-methoxy-11-oxo-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]phenyl]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carboxylate
• CAS: 1383714-45-1
• 化学式: C₄₂H₄₄N₈O₈
• 分子量: 788.86
• InChiKey: CWNHUZFYXNCMKX-PMERELPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  58
• 可旋转键数：
  14
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  180
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethan-1-one 在 四氢吡咯 、 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 sodium methylate 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 、 sodium hydroxide 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 23.83h， 生成 (S)-methyl 4-(4-(4-(4-(4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)butanamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate
  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

• [EN] PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZÉPINES
  申请人：SPIROGEN SARL

  公开号：WO2013164593A1

  公开（公告）日：2013-11-07

  Pyrrolobenzodiazepine (PBDs) having a (1-methyl-1H-pyrrol-3- yl)phenyl based amino residue were found to be highly effective compounds having improved cytotoxicity ad DNA binding properties.

  发现具有（1-甲基-1H-吡咯-3-基）苯基氨基残基的吡咯苯并二氮杂环烃（PBDs）是具有改善的细胞毒性和DNA结合性能的高效化合物。
• PYRROLOBENZODIAZEPINES
  申请人：SPIROGEN SÀRL

  公开号：US20150133435A1

  公开（公告）日：2015-05-14

  Pyrrolobenzodiazepine (PBDs) having a (1-methyl-1H-pyrrol-3-yl)phenyl based amino residue were found to be highly effective compounds having improved cytotoxicity ad DNA binding properties.

  发现具有基于(1-甲基-1H-吡咯-3-基)苯基氨基残基的吡咯并苯二氮平（PBDs）是高效化合物，具有改善的细胞毒性和DNA结合性能。
• US9376440B2
  申请人：——

  公开号：US9376440B2

  公开（公告）日：2016-06-28