2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate | 550355-97-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate
• 英文别名: 2,2,2-trichloroethyl (S)-6-(5-(((allyloxy)carbonyl)amino)-4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-2-methoxyphenoxy)hexanoate；2,2,2-trichloroethyl 6-[4-[(2S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-2-methoxy-5-(prop-2-enoxycarbonylamino)phenoxy]hexanoate
• CAS: 550355-97-0
• 化学式: C₂₅H₃₃Cl₃N₂O₈
• 分子量: 595.905
• InChiKey: SGLNWKOAASLGFD-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  38
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate 在 四氢吡咯 、 四(三苯基膦)钯 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.5h， 生成 2,2,2-trichloroethyl 6-{[(11aS)-7-methoxy-5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy}hexanoate
  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
• 作为产物：
  描述：

  6-溴己酰氯 在 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate
  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

• [EN] ANTIBODIES AND IMMUNOCONJUGATES<br/>[FR] ANTICORPS ET IMMUNOCONJUGUÉS
  申请人：GENENTECH INC

  公开号：WO2016205176A1

  公开（公告）日：2016-12-22

  The invention provides immunoconjugates and methods of using the same.

  这项发明提供了免疫结合物和使用方法。
• ANTI-HER2 ANTIBODIES AND IMMUNOCONJUGATES
  申请人：Genentech, Inc.

  公开号：US20160096893A1

  公开（公告）日：2016-04-07

  The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

  这项发明提供了抗HER2抗体和免疫偶联物，以及使用它们的方法。
• Antibodies and immunoconjugates
  申请人：Genentech, Inc.

  公开号：US10017577B2

  公开（公告）日：2018-07-10

  The invention provides immunoconjugates and methods of using the same.

  本发明提供了免疫结合剂及其使用方法。
• Anti-HER2 antibodies and immunoconjugates
  申请人：Genentech, Inc.

  公开号：US10179820B2

  公开（公告）日：2019-01-15

  The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

  本发明提供了抗 HER2 抗体和免疫结合剂及其使用方法。
• [EN] PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF<br/>[FR] COMPOSÉS PEPTIDOMIMÉTIQUES ET CONJUGUÉS ANTICORPS-MÉDICAMENT DE CEUX-CI
  申请人：GENENTECH INC

  公开号：WO2015095227A3

  公开（公告）日：2015-12-10