6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylic acid ethyl ester | 3306-93-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylic acid ethyl ester
• 英文别名: ethyl 6,11-dioxo-6,11-dihydrobenzo[f]pyrido[1,2-a]indole-12-carboxylate；6,11-Dioxo-12-naphtho[2,3-b]indolizinecarboxylic acid ethyl ester；ethyl 6,11-dioxonaphtho[2,3-b]indolizine-12-carboxylate
• CAS: 3306-93-2
• 化学式: C₁₉H₁₃NO₄
• mdl: MFCD02249874
• 分子量: 319.317
• InChiKey: RCDIUAFMNCXJRV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 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：

  6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylic acid ethyl ester 在 氯化亚砜 、 N,N-二甲基甲酰胺 、 potassium hydroxide 作用下， 以 四氯化碳 、 异丙醇 、 乙腈 为溶剂， 生成 isopropyl 6,11-dioxo-6,11- dihydrobenzo[f]pyrido[1,2-a]indole-12-carboxylate
  参考文献：
  名称：

  6,11-Dioxobenzo[f]pyrido[1,2-a]indoles Kill Mycobacterium tuberculosis by Targeting Iron–Sulfur Protein Rv0338c (IspQ), A Putative Redox Sensor

  摘要：

  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.

  DOI：

  10.1021/acsinfecdis.0c00531
• 作为产物：
  描述：

  2-吡啶乙酸乙酯 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 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxylic acid ethyl ester
  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

• Synthesis, cytotoxic activities and structure–activity relationships of topoisomerase I inhibitors: Indolizinoquinoline-5,12-dione derivatives
  作者：Yu Cheng、Lin-Kun An、Ning Wu、Xiao-Dong Wang、Xian-Zhang Bu、Zhi-Shu Huang、Lian-Quan Gu

  DOI：10.1016/j.bmc.2008.02.036

  日期：2008.4

  indolizinoquinoline-5,12-dione derivatives (IQDs) are synthesized and evaluated for their cytotoxic activities toward human lung adenocarcinoma (GLC-82), large-cell lung carcinoma (NCI-H460), promyelocytic leukemia (HL-60) and breast carcinoma (MCF-7) cells by MTT method. Most of the IQDs show significant cytotoxic potency. In addition, the evaluation of structure-activity relationships indicated that the incorporation

  合成了一系列吲哚并喹啉-5,12-二酮衍生物（IQDs），并评估了它们对人肺腺癌（GLC-82），大细胞肺癌（NCI-H460），早幼粒细胞白血病（HL-60）的细胞毒活性。 MTT法检测乳腺癌细胞（MCF-7）。大多数IQD显示出显着的细胞毒性潜能。此外，对结构活性关系的评估表明，在C或D环上引入吸电子取代基将明显增强目标化合物的活性。还测量了拓扑异构酶I的抑制活性。
• 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。
• Design, synthesis and structure-activity relationship study of novel naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1 inhibitors
  作者：Rui Yang、Yu Chen、Liangkun Pan、Yanyan Yang、Qiang Zheng、Yue Hu、Yuxi Wang、Liangren Zhang、Yang Sun、Zhongjun Li、Xiangbao Meng

  DOI：10.1016/j.bmc.2018.08.028

  日期：2018.9

  Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant

  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。
• 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。
• Synthesis of polycyclic indolizine derivatives via one-pot tandem reactions of N-ylides with dichloro substituted α,β-unsaturated carbonyl compounds
  作者：Yun Liu、Hua-You Hu、Qing-Jian Liu、Hong-Wen Hu、Jian-Hua Xu

  DOI：10.1016/j.tet.2006.12.050

  日期：2007.2

  Convenient and regioselective syntheses of 1,2-annulated, and 1,2-, 5,6- and 1,2-, 7,8-bisannulated polycyclic indolizine derivatives have been achieved by one-pot tandem reactions of cyclic N-ylides derived from the corresponding N-substituted pyridinium, quinolinium, and isoquinolinium salts 1–3 with dichloro substituted α,β-unsaturated carbonyl compounds 4–7. The reactions of the N-ylides with 2

  通过一锅串联的衍生自环状N酰基的串联反应可以方便地和区域选择性地合成1,2-环和1,2-，5,6-和1,2-，7,8-双环的多吲哚嗪衍生物从相应的ñ取代的吡啶鎓，喹啉鎓，和异喹啉盐1 - 3与二氯取代的α，β不饱和羰基的化合物4 - 7。所述的反应Ñ -ylides与2,3- dichloroindenone 4，3,4- dichlorocoumarin 5，和4a，6,7,8a四氯-1,4- methanonaphthalene -5,8-二酮6依次进行[3 + 2]环加成反应，并从环加合物中除去氯化氢。另一方面，N-酰基化物与2,3-二氯-1,4-萘醌7的反应是通过新的反应顺序进行的，得到的产物为15 – 17。

表征谱图