methyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido [1,2-a]indole-12-carboxylate | 98596-13-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: methyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido [1,2-a]indole-12-carboxylate
• 英文别名: methyl 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylate；methyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-12-carboxylate；12-methoxycarbonylbenzo[f]pyrido[1,2-a]indole-6,11-dione；6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylic acid methyl ester；6,11-Dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indol-12-carbonsaeure-methylester；6,11-dihydro-6,11-dioxo-naphth[2,3-b]indolizine-12-carboxylic acid, methyl ester；Methyl 6,11-dioxonaphtho[2,3-b]indolizine-12-carboxylate
• CAS: 98596-13-5
• 化学式: C₁₈H₁₁NO₄
• 分子量: 305.29
• InChiKey: HJDHYWBGLVTHKF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  64.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido [1,2-a]indole-12-carboxylate 在 4-二甲氨基吡啶 、 水 、 potassium carbonate 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 isopropyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido[1,2-a]indole-12-carboxylate
  参考文献：
  名称：

  作为IDO1抑制剂的新型萘并吲哚嗪和吲哚嗪喹啉-5,12-二酮衍生物的设计、合成和构效关系研究

  摘要：

  吲哚胺 2,3-双加氧酶 1 (IDO1) 被认为是癌症免疫治疗的一个有希望的靶点。迄今为止，许多萘醌衍生物已被报道为 IDO1 抑制剂。在此，合成了两个系列的萘醌衍生物，naphthoindolizine 和 indolizinoquinoline-5,12-dione 衍生物，并评估了它们的 IDO1 抑制活性。与色氨酸 2,3-双加氧酶 (TDO) 相比，大多数目标化合物对 IDO1 显示出显着的抑制效力和高选择性。还总结了构效关系。最有效的化合物5c（IC 50 23 nM，IDO1 酶）和5b'（IC 50 372 nM，HeLa 细胞）被鉴定为有前景的先导化合物。

  DOI：

  10.1016/j.bmc.2018.08.028
• 作为产物：
  描述：

  2-吡啶乙酸甲酯 在 对甲苯磺酰叠氮 、 [ruthenium(II)(η⁶-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]₂ 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 邻二氯苯 、 乙腈 为溶剂， 反应 24.0h， 生成 methyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido [1,2-a]indole-12-carboxylate
  参考文献：
  名称：

  吡啶并三唑与萘醌和吲哚的环化反应：苯并[f]吡啶并[1,2-a]吲哚和吲哚并[3,2-b]吲哚的合成

  摘要：

  钌催化的吡啶并三唑与萘醌的脱氮环化提供了苯并[ f ]吡啶并[1,2- a ]吲哚衍生物的良好到优异的产率。而在 PivOH 和 oxone 存在下，吡啶并三唑与吲哚一起在无金属条件下产生吲哚并 [3,2- b ] 吲哚。醌环化通过钌-卡宾中间体进行，而吲哚环化可以通过重氮-吡啶鎓中间体进行。对照实验表明两种转化都遵循离子机制。

  DOI：

  10.1002/adsc.202100965

文献信息

• Copper(II)-Catalyzed Carbon–Carbon Triple Bond Cleavage of Internal Alkynes for the Synthesis of Annulated Indolizines
  作者：Jinwei Sun、Fuyao Wang、Huayou Hu、Xiangshan Wang、Hui Wu、Yun Liu

  DOI：10.1021/jo500456d

  日期：2014.5.2

  Cleavage of C≡C bond in butynedioates via copper(II)-catalyzed reaction has been achieved, leading to the synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones in high yields by one-pot three-component reactions. In this unprecedented C≡C bond cleavage reaction of internal alkynes, both fragments from the alkyne are successively incorporated into the products.

  通过铜（II）催化的反应实现了对丁炔中C≡C键的裂解，从而导致高收率的苯并[ f ]吡啶并[1,2- a ]吲哚-6,11-二酮的单-合成。锅三成分反应。在内部炔烃的这种前所未有的C≡C键裂解反应中，来自炔烃的两个片段均先后结合到产物中。
• Copper(II)-Catalyzed Synthesis of Benzo[<i>f</i>]pyrido[1,2-<i>a</i>]indole-6,11-dione Derivatives via Naphthoquinone Difunctionalization Reaction
  作者：Yun Liu、Jin-Wei Sun

  DOI：10.1021/jo2023312

  日期：2012.1.20

  and pyridine (or isoquinoline) via sp2–C–H difunctionalization of naphthoquinone followed by intramolecular cyclization and oxidative aromatization. In an attempt to expand the reaction scope and to help clarify the reaction mechanism, 1,3-dicarbonyl compounds are used in place of acyl bromides to take part in this reaction, and the benzo[f]pyrido[1,2-a]indole-6,11-diones derivatives are also obtained

  苯并[ f ]吡啶基[1,2 - a ]吲哚-6,11-二酮通过铜（II）催化的酰基溴，1,4-萘醌和吡啶的三组分反应（或异喹啉）通过萘醌的sp 2 -CH双官能化，然后进行分子内环化和氧化芳构化。为了扩大反应范围并澄清反应机理，使用1,3-二羰基化合物代替酰基溴参与了该反应，并使用了苯并[ f ]吡啶基[1,2- a ]还以优异的产率获得了吲哚-6，11-二酮衍生物。
• Microwave-Assisted Multicomponent Synthesis of Aza-, Diaza-, Benzo-, and Dibenzofluorenedione Derivatives
  作者：Andrea Defant、Graziano Guella、Ines Mancini

  DOI：10.1080/00397910802044249

  日期：2008.8.18

  Abstract A microwave procedure was efficiently applied to the synthesis of a series of heteropolycyclic compounds with known or potential biological activities. Antitumor amide 3was obtained in a few minutes and with high yields through a solventless, one-pot cyclization, followed by treatment with the suitable amine. This method was also used to access tetracyclic aza-compounds 5/6, where their selective

  摘要 微波方法有效地应用于合成一系列具有已知或潜在生物活性的杂多环化合物。通过无溶剂的一锅环化，然后用合适的胺处理，在几分钟内以高收率获得了抗肿瘤酰胺 3。该方法还用于获得四环氮杂化合物 5/6，其中在无溶剂条件下或通过改变溶剂，在固体存在下研究它们作为 N,N-syn 和 N,N-反区域异构体的选择性形成载体和催化量的环保金属盐。在这种情况下，通过微波辐射改进了使用预制吡啶鎓或异喹啉鎓叶立德在常规加热下对类似多环化合物的热访问，并扩展到二氮杂酯的合成。在任何情况下，一锅三组分环化比 N-ylide 序列的原子效率更高。
• Synthesis andIn Vitro Cytotoxicity Evaluation of Novel Naphthindolizinedione Derivatives
  作者：Andrea Defant、Graziano Guella、Ines Mancini

  DOI：10.1002/ardp.200600160

  日期：2007.3

  were evaluated in the NCI panel of human tumour cell lines, from which 6,11‐dioxo‐6,11‐dihydro‐benzo[f]pyrido[1,2‐a]indole‐(2‐dimethylamino‐ethyl)‐12‐carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 μM. Moreover, its cytotoxicity against

  根据 Moore 和 Pindur 理论设计了新型 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide 衍生物和相应的 7,10-dihydroxy类似物基于与已知抗肿瘤药物如玫瑰树碱、柔红霉素、米托蒽醌和 9-氨基吖啶-4甲酰胺衍生物的结构相似性合成。这些化合物，包括酰胺侧链的结构变化，在人类肿瘤细胞系的 NCI 小组中进行了评估，其中 6,11-二氧-6,11-二氢-苯并[f]吡啶并[1,2-a]吲哚-(2-二甲氨基-乙基)-12-甲酰胺11a被发现是该系列中最有效的药物。它对白血病、结肠癌和肾癌细胞系显示出良好的选择性，具有显着的 GI50 值，从低于 10 nM 到 0.2 μM。而且，
• 6,11-Dioxobenzo[<i>f</i>]pyrido[1,2-<i>a</i>]indoles Kill <i>Mycobacterium tuberculosis</i> by Targeting Iron–Sulfur Protein Rv0338c (IspQ), A Putative Redox Sensor
  作者：Rita Székely、Monica Rengifo-Gonzalez、Vinayak Singh、Olga Riabova、Andrej Benjak、Jérémie Piton、Mena Cimino、Etienne Kornobis、Valerie Mizrahi、Kai Johnsson、Giulia Manina、Vadim Makarov、Stewart T. Cole

  DOI：10.1021/acsinfecdis.0c00531

  日期：2020.11.13

  Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.

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