methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3- carboxylate | 380895-64-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3- carboxylate
• 英文别名: methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate；methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• CAS: 380895-64-7
• 化学式: C₂₁H₂₂N₂O₄
• 分子量: 366.417
• InChiKey: NUBFFNNCFFBKKI-LPHOPBHVSA-N

物化性质

• 沸点：
  535.0±50.0 °C(Predicted)
• 密度：
  1.244±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  72.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3- carboxylate 在 碳酸氢钠 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 17.0h， 生成 (6S,12aS)-2-tert-butyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  一种新型的获取基于芳基和杂芳基的β-咔啉的PDE5抑制剂的方法。

  摘要：

  从先前报道的先导化合物GR30040X（在C-5具有4-吡啶基环的乙内酰脲四氢-β-咔啉衍生物）开始，制备了一系列结构上相关的四氢-β-咔啉衍生物。将四氢-β-咔啉骨架与乙内酰脲或哌嗪二酮环稠合，连接至C-5或C-6的侧基芳基变为3，4-二甲氧基苯基或3-吡啶基环；在末端环上引入了不同的N-取代基，即直链乙基，支链叔叔。丁基和对氯苯基而不是铅化合物的正丁基。制备了目标四氢-β-咔啉衍生物的所有四种可能的非对映异构体，通过柱色谱法进行了分离，并研究了这些立体化学操作的重要性。评价合成的化合物对PDE5的抑制作用。与PDE5相比，IC50为0.14-4.99μM时，具有七个具有明显抑制活性的命中值。

  DOI：

  10.2174/157340610793563992
• 作为产物：
  描述：

  L-色氨酸 在 乙酰氯 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 96.0h， 生成 methyl (1S,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3- carboxylate
  参考文献：
  名称：

  一种新型的获取基于芳基和杂芳基的β-咔啉的PDE5抑制剂的方法。

  摘要：

  从先前报道的先导化合物GR30040X（在C-5具有4-吡啶基环的乙内酰脲四氢-β-咔啉衍生物）开始，制备了一系列结构上相关的四氢-β-咔啉衍生物。将四氢-β-咔啉骨架与乙内酰脲或哌嗪二酮环稠合，连接至C-5或C-6的侧基芳基变为3，4-二甲氧基苯基或3-吡啶基环；在末端环上引入了不同的N-取代基，即直链乙基，支链叔叔。丁基和对氯苯基而不是铅化合物的正丁基。制备了目标四氢-β-咔啉衍生物的所有四种可能的非对映异构体，通过柱色谱法进行了分离，并研究了这些立体化学操作的重要性。评价合成的化合物对PDE5的抑制作用。与PDE5相比，IC50为0.14-4.99μM时，具有七个具有明显抑制活性的命中值。

  DOI：

  10.2174/157340610793563992

文献信息

• Biological Studies and Target Engagement of the 2-<i>C</i>-Methyl-<scp>d</scp>-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1<i>R</i>,3<i>S</i>)-MMV008138 and Analogs
  作者：Maryam Ghavami、Emilio F. Merino、Zhong-Ke Yao、Rubayet Elahi、Morgan E. Simpson、Maria L. Fernández-Murga、Joshua H. Butler、Michael A. Casasanta、Priscilla M. Krai、Maxim M. Totrov、Daniel J. Slade、Paul R. Carlier、Maria Belen Cassera

  DOI：10.1021/acsinfecdis.7b00159

  日期：2018.4.13

  to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized

  疟疾仍然是世界上最致命的疾病之一，耐药性寄生虫的出现一直是威胁。疟原虫寄生虫利用甲基赤藓糖醇磷酸酯（MEP）途径来合成异戊烯基焦磷酸酯（IPP）和二甲基烯丙基焦磷酸酯（DMAPP），这对于寄生虫的生长至关重要。以前，我们和其他人发现，疟疾框化合物MMV008138靶向于原生质体，并且该化合物对寄生虫的生长抑制作用可以通过补充IPP来逆转。进一步的工作表明，MMV008138靶向2- C-甲基-d酶。MEP途径中的-赤藓糖醇4-磷酸胞苷转移酶（IspD），可将MEP和胞苷三磷酸（CTP）转化为胞苷二磷酸甲基赤藓糖醇（CDP-ME）和焦磷酸。在这项工作中，我们试图通过探索MMV008138类似物抑制Pf IspD重组酶的能力来深入了解结构与活性之间的关系。这里，我们报告Pf的ISPD抑制数据用于膦胺霉素（FOS）和19个以前公开的类似物和报告寄生虫生长和Pf的ISPD抑制数据用于MMV0081
• DNA-binding affinity and anticancer activity of β-carboline–chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis
  作者：Nagula Shankaraiah、K.P. Siraj、Shalini Nekkanti、Vunnam Srinivasulu、Pankaj Sharma、Kishna Ram Senwar、Manda Sathish、M.V.P.S. Vishnuvardhan、Sistla Ramakrishna、Chetna Jadala、Narayana Nagesh、Ahmed Kamal

  DOI：10.1016/j.bioorg.2015.02.007

  日期：2015.4

  A new series of DNA-interactive beta-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 ( lung adenocarcinoma) cell lines with IC50 values lower than 10 mu M. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 mu M. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in Delta T-m of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies. (C) 2015 Elsevier Inc. All rights reserved.
• Discovery of novel phosphatidylcholine-specific phospholipase C drug-like inhibitors as potential anticancer agents
  作者：Chatchakorn Eurtivong、Lisa I. Pilkington、Michelle van Rensburg、Reuben M. White、Harpreet Kaur Brar、Shaun Rees、Emily K. Paulin、Chris Sun Xu、Nabangshu Sharma、Ivanhoe K.H. Leung、Euphemia Leung、David Barker、Jóhannes Reynisson

  DOI：10.1016/j.ejmech.2019.111919

  日期：2020.2

  Phosphatidylcholine-specific phospholipase C (PC-PLC) is a promising target for new anticancer treatment. Herein, we report our work in the discovery of novel drug-like PC-PLC inhibitors. Virtual screening led to the identification of promising hits from four different structural series that contain the molecular scaffold of benzenesulphonamides (10), pyrido[3,4-b]indoles (22), morpholinobenzoic acid (84) and benzamidobenzoic acid (80). 164 structural analogues were tested to investigate the chemical space around the hit series and to generate preliminary structurally activity relationships (SAR). Two of the pyrido[3,4-b]indoles (22_10 and 22_15) had comparable or better potency as D609, an established but non-drug-like PC-PLC inhibitor. Furthermore, three morpholinobenzoic acids (84, 84_4 and 84_5) had superior potency than D609. Therefore, this study paves the way towards the development of drug-like PL-PLC inhibitors as potential anticancer agents. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: an improved asymmetric synthesis of tadalafil from l-tryptophan
  作者：Jing Dong、Tian-Zhuo Meng、Xiao-Xin Shi、Wen-Hui Zou、Xia Lu

  DOI：10.1016/j.tetasy.2013.06.006

  日期：2013.8

  An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-beta-carbolines (THBCs) into (15,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (15,3S)-cis-1,2,3-trisubstituted THBCs 2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (15,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis (R)) starting from natural and less expensive L-tryptophan was developed. (C) 2013 Elsevier Ltd. All rights reserved.
• Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities
  作者：Wen Wen、Jiadong Hu、Chenxi Wang、Rui Yang、Yabo Zhang、Baibei Huang、Tingting Qiao、Jiayun Wang、Xin Chen

  DOI：10.1016/j.bmcl.2024.129670

  日期：2024.4