(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
• 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.