(11aS)-4-(7-methoxy-5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)butanoic acid | 909415-18-5

• 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: (11aS)-4-(7-methoxy-5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)butanoic acid
• 英文别名: 4-[[(6aS)-2-methoxy-6,11-dioxo-6a,7,8,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoic acid
• CAS: 909415-18-5
• 化学式: C₁₇H₂₀N₂O₆
• 分子量: 348.356
• InChiKey: YXUWBPAQLJQODT-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (11aS)-4-(7-methoxy-5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)butanoic acid 、 H-Py-Py-Py-OMe hydrochloride 在 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 二氯甲烷 为溶剂， 反应 24.0h， 生成 methyl 4-[[4-[[4-[4-[(2-methoxy-6,11-dioxo-6a,7,8,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)oxy]butanoylamino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carboxylate
  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
• 作为产物：
  描述：

  methyl (2S)-N-[4-benzyloxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxylate 在 palladium on activated charcoal 氢气 、 potassium carbonate 作用下， 以 乙醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 5.5h， 生成 (11aS)-4-(7-methoxy-5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)butanoic acid
  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

• Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines
  作者：Pietro Picconi、Charlotte K. Hind、J. Mark Sutton、Khondaker Miraz Rahman

  DOI：10.3390/antibiotics11121770

  日期：——

  It is urgent to find new antibiotic classes against multidrug-resistant bacteria as the rate of discovery of new classes of antibiotics has been very slow in the last 50 years. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad-spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and noncytotoxic dilactam analogues to understand the structure-activity relationship further and improve the safety potential of this class. The synthesised compounds were tested against panels of multidrug-resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 to 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues. At the same time, they were found to be inactive against MDR Gram-negative bacteria, with a MIC > 32 mg/L, compared to a MIC of 0.5 to 32 mg/L for imine analogues. A molecular modelling study suggests that the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests that the presence of N10-C11 imine moiety is crucial for the broad-spectrum activity of pyrrolobenzodiazepines.

  在过去的50年中，新类抗生素的发现速度非常缓慢，因此迫切需要寻找新的抗多药耐药菌类抗生素。最近，已经发现了一种新的广谱抗生素类别——含有C8-连接脂肪族杂环的吡咯并苯并二氮杂环衍生物（PBDs），对革兰氏阴性菌具有活性。为了进一步了解结构活性关系并提高这一类药物的安全性潜力，报告的主导吡咯并苯并二氮杂环化合物的活性亚胺基团已被替换为酰胺基团，从而获得了非DNA结合和非细胞毒性的双内酰胺类似物。这些合成化合物被测试用于多药耐药革兰氏阳性和革兰氏阴性菌的菌株组，包括世界卫生组织优先病原体。对于多药耐药革兰氏阳性菌，双内酰胺类似物的最小抑菌浓度范围为4至32 mg/L，而相应的亚胺类似物的最小抑菌浓度为0.03至2 mg/L。同时，它们被发现对多药耐药革兰氏阴性菌无活性，最小抑菌浓度>32 mg/L，而亚胺类似物的最小抑菌浓度为0.5至32 mg/L。分子模拟研究表明，亚胺功能的缺失也影响了PBDs与DNA酶的相互作用。这项研究表明，N10-C11亚胺基团的存在对于吡咯并苯并二氮杂环的广谱活性至关重要。
• 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.