methyl (S)-4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: methyl (S)-4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate
• 英文别名: methyl 4-[[(6aS)-2-methoxy-11-oxo-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoate
• 化学式: C₁₈H₂₂N₂O₅
• 分子量: 346.383
• InChiKey: NVPXDWFXBCBRSO-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  77.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (S)-4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate 、 丙酮 在 四氢吡咯 作用下， 反应 72.0h， 生成 methyl 4-(((11S,11aS)-7-methoxy-5-oxo-11-(2-oxopropyl)-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate 、 methyl 4-(((11R,11aS)-7-methoxy-5-oxo-11-(2-oxopropyl)-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate
  参考文献：
  名称：

  失去细胞毒性的吡咯并苯二氮卓 (PBD) 的新型 C11-丙酮加合物的形成

  摘要：

  在丙酮存在下，吡咯并苯二氮卓 (PBD) 化合物的色谱纯化过程中观察到了吡咯烷催化形成的新型非对映体 C11-丙酮加合物。探索了该反应的机理并充分表征了所获得的加合物。还发现 Talirine 是抗体-药物偶联物 (ADC) 伐达妥昔单抗 talirine 的细胞毒性有效载荷元素，在类似条件下也可形成双加合物。对修饰的 PBD 化合物的细胞毒性评估证实它们没有细胞毒性，这与 DNA 相互作用的 N10-C11 亚胺功能的丧失一致。除了这里报告的新化学，鉴于目前临床上基于 PBD 的 ADC 的数量，这一观察结果对于大规模生产基于 PBD 的产品可能很重要。

  DOI：

  10.1055/s-0036-1591552
• 作为产物：
  描述：

  4-溴丁酸甲酯 在 palladium on activated charcoal 四氢吡咯 、 吡啶 、 potassium permanganate 、 四(三苯基膦)钯 、 草酰氯 、 氢气 、 硝酸 、 乙酸酐 、 potassium carbonate 、 对甲苯磺酸 、 二甲基亚砜 、 三乙胺 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， -40.0~20.0 ℃ 、275.79 kPa 条件下， 反应 58.5h， 生成 methyl (S)-4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoate
  参考文献：
  名称：

  Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(N-methylpyrrole) Conjugates

  摘要：

  A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXW(z) (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/ nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.

  DOI：

  10.1021/jm051199z

文献信息

• Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(<i>N</i>-methylpyrrole) Conjugates
  作者：Geoff Wells、Christopher R. H. Martin、Philip W. Howard、Zara A. Sands、Charles A. Laughton、Arnaud Tiberghien、Chi Kit Woo、Luke A. Masterson、Marissa J. Stephenson、John A. Hartley、Terence C. Jenkins、Steven D. Shnyder、Paul M. Loadman、Michael J. Waring、David E. Thurston

  DOI：10.1021/jm051199z

  日期：2006.9.1

  A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXW(z) (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/ nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
• Formation of a Novel C11-Acetone Adduct of a Pyrrolobenzodiazepine (PBD) with Loss of Cytotoxicity
  作者：David Thurston、David Corcoran、Pietro Picconi、Connie Chui、George Procopiou、Ilona Pysz、Khondaker Rahman

  DOI：10.1055/s-0036-1591552

  日期：2018.5

  The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed during the chromatographic purification of pyrrolobenzodiazepine (PBD) compounds in the presence of acetone. The mechanism of this reaction was explored and the adducts obtained fully characterised. Talirine, the cytotoxic payload element of the antibody-drug conjugate (ADC) vadastuximab talirine, was also

  在丙酮存在下，吡咯并苯二氮卓 (PBD) 化合物的色谱纯化过程中观察到了吡咯烷催化形成的新型非对映体 C11-丙酮加合物。探索了该反应的机理并充分表征了所获得的加合物。还发现 Talirine 是抗体-药物偶联物 (ADC) 伐达妥昔单抗 talirine 的细胞毒性有效载荷元素，在类似条件下也可形成双加合物。对修饰的 PBD 化合物的细胞毒性评估证实它们没有细胞毒性，这与 DNA 相互作用的 N10-C11 亚胺功能的丧失一致。除了这里报告的新化学，鉴于目前临床上基于 PBD 的 ADC 的数量，这一观察结果对于大规模生产基于 PBD 的产品可能很重要。