(11aS)-8-(3-{4-[5-(4-ethoxycarbonyl-thiazol-2-ylcarbamoyl)-1-methyl-1H-pyrrol-3-ylcarbamoyl]thiazol-2-ylcarbamoyl}propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester | 1448438-42-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (11aS)-8-(3-{4-[5-(4-ethoxycarbonyl-thiazol-2-ylcarbamoyl)-1-methyl-1H-pyrrol-3-ylcarbamoyl]thiazol-2-ylcarbamoyl}propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
• CAS: 1448438-42-3
• 化学式: C₄₂H₄₈N₈O₁₂S₂
• 分子量: 921.022
• InChiKey: BCASMIMVGGLJHJ-SBNSHCHQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.04
• 重原子数：
  64.0
• 可旋转键数：
  17.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  231.08
• 氢给体数：
  3.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  (11aS)-8-(3-{4-[5-(4-ethoxycarbonyl-thiazol-2-ylcarbamoyl)-1-methyl-1H-pyrrol-3-ylcarbamoyl]thiazol-2-ylcarbamoyl}propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester 在 四氢吡咯 、 四(三苯基膦)钯 作用下， 以 二氯甲烷 为溶剂， 以9%的产率得到ethyl 4-{[4-(4-(7-methoxy-5-oxo-2,3,5,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butyrylaminothiazole-4-carbonylamino)-1-methyl-1H-pyrrole-2-carbonyl]-amino}thiazole-4-carboxylate
  参考文献：
  名称：

  An Extended Pyrrolobenzodiazepine–Polyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

  摘要：

  The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase II alpha results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD-DNA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.

  DOI：

  10.1021/jm4001852
• 作为产物：
  描述：

  4-(Boc-氨基)-1-甲基吡咯-2-羧酸 在 盐酸 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 187.0h， 生成 (11aS)-8-(3-{4-[5-(4-ethoxycarbonyl-thiazol-2-ylcarbamoyl)-1-methyl-1H-pyrrol-3-ylcarbamoyl]thiazol-2-ylcarbamoyl}propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
  参考文献：
  名称：

  An Extended Pyrrolobenzodiazepine–Polyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

  摘要：

  The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase II alpha results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD-DNA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.

  DOI：

  10.1021/jm4001852