allyl (11aS)-8-({6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indol-3-yl]-6-oxohexyl}oxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | 550356-30-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: allyl (11aS)-8-({6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indol-3-yl]-6-oxohexyl}oxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate
• 英文别名: prop-2-enyl (6aS)-3-[6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydrobenzo[e]indol-3-yl]-6-oxohexoxy]-6-hydroxy-2-methoxy-11-oxo-6a,7,8,9-tetrahydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• CAS: 550356-30-4
• 化学式: C₃₆H₄₀ClN₃O₈
• 分子量: 678.182
• InChiKey: WKEYXMDSENYWEB-RWTQNFDGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  48
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  129
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  allyl (11aS)-8-({6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indol-3-yl]-6-oxohexyl}oxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate 在 potassium carbonate 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 3.0h， 以91%的产率得到allyl (11aS)-11-hydroxy-7-methoxy-5-oxo-8-({6-oxo-6-[(1aS,9bR)-5-oxo-1a,2-dihydro-1H-benzo[e]cyclopropa[c]indol-3(5H)-yl]hexyl}oxy)-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate
  参考文献：
  名称：

  掺有氨基杜鹃霉素的氨基衍生物aminoCBI的DNA小沟交联剂的类似物：合成，细胞毒性和潜在的抗体-药物缀合物的有效负载量。

  摘要：

  Pd催化的胺化方法用于将seco-CBI（杜卡霉素天然产物的烷基化亚基的合成类似物）从苯酚转化为氨基形式。这允许对氨基CBI的更有效的S对映异构体的有效对映选择性访问，并将其并入DNA小沟交联剂的类似物中。在一组九种人类肿瘤细胞系中进行的评估显示，含有氨基CBI的双功能药物通常比其酚CBI类似物的细胞毒性更小，并且更容易受到P-糖蛋白介导的抗药性的影响。但是，所有双功能剂都是有效的细胞毒素，某些在亚pM IC50范围内，其体外特性与已建立的以微管为目标的ADC有效负载相比具有优势。

  DOI：

  10.1016/j.bmc.2016.09.068
• 作为产物：
  描述：

  2,2,2-trichloroethyl 6-bromohexanoate 在 甲酸 、 2,4-滴二甲胺盐 、 potassium carbonate 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 锌 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.5h， 生成 allyl (11aS)-8-({6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indol-3-yl]-6-oxohexyl}oxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate
  参考文献：
  名称：

  Unsymmetrical DNA Cross-Linking Agents:  Combination of the CBI and PBD Pharmacophores

  摘要：

  A set of 10 compounds, each combining the seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (seco-CBI) and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) pharmacophores, was designed and prepared. These compounds were anticipated to cross-link between N3 of adenine and N2 of guanine in the minor groove of DNA. The compounds, which differ in the chain length separating the two alkylation subunits, and the configuration of the CBI portion, showed great variation in cellular toxicity (over 4 orders of magnitude in a cell line panel) with the most potent example exhibiting IC50S in the pM range. Cytotoxicity correlated with the ability of the compounds to cross-link naked DNA. Cross-linking was also observed in living cells, at much lower concentrations than for a related symmetrical PBD dimer. A thermal cleavage assay was used to assess sequence selectivity, demonstrating that the CBI portion controlled the alkylation sites, while the PBD substituent increased the overall efficiency of alkylation. Several compounds were tested for in vivo activity using a tumor growth delay assay against WiDr human colon carcinoma xenografts, with one compound (the most cytotoxic and most efficient cross-linker) showing a statistically significant increase in survival time following a single iv dose.

  DOI：

  10.1021/jm020526p

文献信息

• Unsymmetrical DNA Cross-Linking Agents:  Combination of the CBI and PBD Pharmacophores
  作者：Moana Tercel、Stephen M. Stribbling、Hilary Sheppard、Bronwyn G. Siim、Kent Wu、Susan M. Pullen、K. Jane Botting、William R. Wilson、William A. Denny

  DOI：10.1021/jm020526p

  日期：2003.5.1

  A set of 10 compounds, each combining the seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (seco-CBI) and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) pharmacophores, was designed and prepared. These compounds were anticipated to cross-link between N3 of adenine and N2 of guanine in the minor groove of DNA. The compounds, which differ in the chain length separating the two alkylation subunits, and the configuration of the CBI portion, showed great variation in cellular toxicity (over 4 orders of magnitude in a cell line panel) with the most potent example exhibiting IC50S in the pM range. Cytotoxicity correlated with the ability of the compounds to cross-link naked DNA. Cross-linking was also observed in living cells, at much lower concentrations than for a related symmetrical PBD dimer. A thermal cleavage assay was used to assess sequence selectivity, demonstrating that the CBI portion controlled the alkylation sites, while the PBD substituent increased the overall efficiency of alkylation. Several compounds were tested for in vivo activity using a tumor growth delay assay against WiDr human colon carcinoma xenografts, with one compound (the most cytotoxic and most efficient cross-linker) showing a statistically significant increase in survival time following a single iv dose.
• Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody–drug conjugates
  作者：Anna C. Giddens、Ho H. Lee、Guo-Liang Lu、Christian K. Miller、Jun Guo、Gail D. Lewis Phillips、Thomas H. Pillow、Moana Tercel

  DOI：10.1016/j.bmc.2016.09.068

  日期：2016.11

  A Pd-catalysed amination method is used to convert seco-CBI, a synthetic analogue of the alkylating subunit of the duocarmycin natural products, from the phenol to amino form. This allows efficient enantioselective access to the more potent S enantiomer of aminoCBI and its incorporation into analogues of DNA minor groove cross-linking agents. Evaluation in a panel of nine human tumour cell lines shows

  Pd催化的胺化方法用于将seco-CBI（杜卡霉素天然产物的烷基化亚基的合成类似物）从苯酚转化为氨基形式。这允许对氨基CBI的更有效的S对映异构体的有效对映选择性访问，并将其并入DNA小沟交联剂的类似物中。在一组九种人类肿瘤细胞系中进行的评估显示，含有氨基CBI的双功能药物通常比其酚CBI类似物的细胞毒性更小，并且更容易受到P-糖蛋白介导的抗药性的影响。但是，所有双功能剂都是有效的细胞毒素，某些在亚pM IC50范围内，其体外特性与已建立的以微管为目标的ADC有效负载相比具有优势。