(11aS)-1,2,3,10,11,11a-hexahydro-9-(benzyloxy)-10-(benzyloxycarbonyl)-5H-pyrrolo<2,1-c><1,4>benzodiazepin-5,11-dione | 125299-56-1

• 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)-1,2,3,10,11,11a-hexahydro-9-(benzyloxy)-10-(benzyloxycarbonyl)-5H-pyrrolo<2,1-c><1,4>benzodiazepin-5,11-dione
• 英文别名: benzyl (S)-9-(benzyloxy)-5,11-dioxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate；benzyl (6aS)-6,11-dioxo-4-phenylmethoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• CAS: 125299-56-1
• 化学式: C₂₇H₂₄N₂O₅
• 分子量: 456.498
• InChiKey: OAFHRVFTHGTBBV-QFIPXVFZSA-N

物化性质

• 熔点：
  50-52 °C
• 沸点：
  662.7±65.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.55
• 重原子数：
  34.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  76.15
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (11aS)-1,2,3,10,11,11a-hexahydro-9-(benzyloxy)-10-(benzyloxycarbonyl)-5H-pyrrolo<2,1-c><1,4>benzodiazepin-5,11-dione 在 sodium tetrahydroborate 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以72%的产率得到(S)-9-Benzyloxy-11-hydroxy-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carboxylic acid benzyl ester
  参考文献：
  名称：

  A tricyclic pyrrolobenzodiazepine produced by Klebsiella oxytoca is associated with cytotoxicity in antibiotic-associated hemorrhagic colitis

  摘要：

  Cytotoxin-producing Klebsiella oxytoca is the causative agent of antibiotic-associated hemorrhagic colitis (AAHC). Recently, the cytotoxin associated with AAHC was identified as tilivalline, a known pentacyclic pyrrolobenzodiazepine (PBD) metabolite produced by K. oxytoca. Although this assertion of tilivalline's role in AAHC is supported by evidence from animal experiments, some key aspects of this finding appear to be incompatible with toxicity mechanisms of known PBD toxins. We therefore hypothesized that K. oxytoca may produce some other uncharacterized cytotoxins. To address this question, we investigated whether tilivalline alone is indeed necessary and sufficient to induce cytotoxicity or whether K. oxytoca also produces other cytotoxins. LC-MS- and NMR-based metabolomic analyses revealed the presence of an abundant tricyclic PBD, provisionally designated kleboxymycin, in the supernatant of toxigenic K. oxytoca strains. Moreover, by generating multiple mutants with gene deletions affecting tilivalline biosynthesis, we show that a tryptophanase-deficient, tilivalline-negative K. oxytoca mutant induced cytotoxicity in vitro similar to tilivalline-positive K. oxytoca strains. Furthermore, synthetic kleboxymycin exhibited greater than 9-fold higher cytotoxicity than tilivalline in TC50 cell culture assays. We also found that the biosynthetic pathways for kleboxymycin and tilivalline appear to overlap, as tilivalline is an indole derivative of kleboxymycin. In summary, our results indicate that tilivalline is not essential for inducing cytotoxicity observed in K. oxytoca-associated AAHC and that kleboxymycin is a tilivalline-related bacterial metabolite with even higher cytotoxicity.

  DOI：

  10.1074/jbc.m117.791558
• 作为产物：
  描述：

  3-羟基-2-氨基苯甲酸 在 叠氮磷酸二苯酯 、 potassium carbonate 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.06h， 生成 (11aS)-1,2,3,10,11,11a-hexahydro-9-(benzyloxy)-10-(benzyloxycarbonyl)-5H-pyrrolo<2,1-c><1,4>benzodiazepin-5,11-dione
  参考文献：
  名称：

  A tricyclic pyrrolobenzodiazepine produced by Klebsiella oxytoca is associated with cytotoxicity in antibiotic-associated hemorrhagic colitis

  摘要：

  Cytotoxin-producing Klebsiella oxytoca is the causative agent of antibiotic-associated hemorrhagic colitis (AAHC). Recently, the cytotoxin associated with AAHC was identified as tilivalline, a known pentacyclic pyrrolobenzodiazepine (PBD) metabolite produced by K. oxytoca. Although this assertion of tilivalline's role in AAHC is supported by evidence from animal experiments, some key aspects of this finding appear to be incompatible with toxicity mechanisms of known PBD toxins. We therefore hypothesized that K. oxytoca may produce some other uncharacterized cytotoxins. To address this question, we investigated whether tilivalline alone is indeed necessary and sufficient to induce cytotoxicity or whether K. oxytoca also produces other cytotoxins. LC-MS- and NMR-based metabolomic analyses revealed the presence of an abundant tricyclic PBD, provisionally designated kleboxymycin, in the supernatant of toxigenic K. oxytoca strains. Moreover, by generating multiple mutants with gene deletions affecting tilivalline biosynthesis, we show that a tryptophanase-deficient, tilivalline-negative K. oxytoca mutant induced cytotoxicity in vitro similar to tilivalline-positive K. oxytoca strains. Furthermore, synthetic kleboxymycin exhibited greater than 9-fold higher cytotoxicity than tilivalline in TC50 cell culture assays. We also found that the biosynthetic pathways for kleboxymycin and tilivalline appear to overlap, as tilivalline is an indole derivative of kleboxymycin. In summary, our results indicate that tilivalline is not essential for inducing cytotoxicity observed in K. oxytoca-associated AAHC and that kleboxymycin is a tilivalline-related bacterial metabolite with even higher cytotoxicity.

  DOI：

  10.1074/jbc.m117.791558

文献信息

• Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline
  作者：Elisabeth Dornisch、Jakob Pletz、Ronald A. Glabonjat、Florian Martin、Christian Lembacher-Fadum、Margit Neger、Christoph Högenauer、Kevin Francesconi、Wolfgang Kroutil、Klaus Zangger、Rolf Breinbauer、Ellen L. Zechner

  DOI：10.1002/anie.201707737

  日期：2017.11.13

  the biosynthesis of tilivalline and show that this nonribosomal peptide assembly pathway initially generates tilimycin, a simple pyrrolobenzodiazepine with cytotoxic properties. Tilivalline results from the non-enzymatic spontaneous reaction of tilimycin with biogenetically generated indole. Through a chemical total synthesis of tilimycin we could corroborate the predictions made about the biosynthesis

  非核糖体肠毒素 tilivalline 是第一个与人类肠道疾病相关的天然吡咯并苯二氮卓类药物。由于产酸克雷伯菌是肠道微生物群的一部分，而吡咯并苯二氮卓类药物会引起结肠炎的发病机制，因此了解替利缬林活性的生物合成和调节非常重要。在这里，我们报告了替利缬林的生物合成，并表明这种非核糖体肽组装途径最初产生替利霉素，一种具有细胞毒性的简单吡咯并苯二氮卓类药物。替利缬氨酸是由替利霉素与生物生成的吲哚发生非酶促自发反应而产生的。通过提利霉素的化学全合成，我们可以证实有关生物合成的预测。人类肠道驻留产酸克雷伯菌产生两种具有不同功能的细胞毒性吡咯并苯二氮卓类药物，对肠道疾病具有重要意义。
• Stereoselective Synthesis of Tilivalline¹
  作者：Tatsuo Nagasaka、Yuji Koseki

  DOI：10.1021/jo972158g

  日期：1998.10.1

  Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified Curtius reactions of 3-substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4, conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole from the less hindered side of 7.
• Stereoselective synthesis of tilivalline
  作者：Tatsuo Nagasaka、Yuji Koseki、Fumiko Hamaguchi

  DOI：10.1016/s0040-4039(00)99602-3

  日期：——
• NAGASAKA, TATSUO;KOSEKI, YUJI;HAMAGUCHI, FUMIKO, TETRAHEDRON LETT., 30,(1989) N4, C. 1871-1872
  作者：NAGASAKA, TATSUO、KOSEKI, YUJI、HAMAGUCHI, FUMIKO

  DOI：——

  日期：——