(+/-) cis-methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate

• 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: (+/-) cis-methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
• 英文别名: methyl (1R,3R)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• 化学式: C₂₁H₂₂N₂O₄
• 分子量: 366.417
• InChiKey: NUBFFNNCFFBKKI-VQIMIIECSA-N

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：

  (+/-) cis-methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 在 碳酸氢钠 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 17.0h， 生成 (6R,12aR)-2-ethyl-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：

  3,4-二甲氧基苯甲醛 在 三氟乙酸 作用下， 以 甲苯 为溶剂， 生成 (+/-) cis-methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
  参考文献：
  名称：

  Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors

  摘要：

  The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00159-8

文献信息

• Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds
  作者：Terence B. Beghyn、Julie Charton、Florence Leroux、Antoine Henninot、Irena Reboule、Paul Cos、Louis Maes、Benoit Deprez

  DOI：10.1021/jm201422e

  日期：2012.2.9

  In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach (J. Med. Chem. 2011, 54 (9), pp 3222-3240). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethozyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.
• Synthesis of Tadalafil Analogues
  作者：Liu‐Tang Wang、Hao Huang、Zhong‐Lin Ye、Yong Wu、Xue‐Chao Wang

  DOI：10.1080/00397910600764626

  日期：2006.9
• 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.
• The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-<i>b</i>]indole-1,4-dione Analogues
  作者：Alain Daugan、Pascal Grondin、Cécile Ruault、Anne-Charlotte Le Monnier de Gouville、Hervé Coste、Jean Michel Linget、Jorge Kirilovsky、François Hyafil、Richard Labaudinière

  DOI：10.1021/jm0300577

  日期：2003.10.1

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
• Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet–Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes
  作者：Sen Xiao、Xia Lu、Xiao-Xin Shi、Yu Sun、Li-Li Liang、Xin-Hong Yu、Jing Dong

  DOI：10.1016/j.tetasy.2009.01.026

  日期：2009.3

  A highly stereoselective Pictet-Spengler reaction of D-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene, and a fine tuning of the ratio of nitromethane and toluene for each epimer Mixture of 2-HCl was necessary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans) 1,3-disubstituted tetrahydro-beta-carbolines 2a-2v were obtained by recrystallization or flash chromatography after neutralization of the corresponding hydrochloride salts cis-2-HCl or trans-2-HCl. (c) 2009 Elsevier Ltd. All rights reserved.