methyl (1S,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate | 1262447-29-9

• 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-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
• 英文别名: (1S,3S)-methyl 1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate；methyl (1S,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• CAS: 1262447-29-9
• 化学式: C₁₉H₁₆Cl₂N₂O₂
• 分子量: 375.254
• InChiKey: GRNZPDVXMDBGHG-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl (1S,3S)-1-(2,4-dichlorophenyl)-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 16.0h， 生成 (6S,12aS)-6-(2,4-dichlorophenyl)-2-methyl-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：

  Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

  摘要：

  New derivatives based upon the tetrahydro-beta-carboline-hydantoin and tetrahydro-beta-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from L-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.

  DOI：

  10.1021/jm100842v
• 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 5.0h， 生成 methyl (1S,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
  参考文献：
  名称：

  Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

  摘要：

  New derivatives based upon the tetrahydro-beta-carboline-hydantoin and tetrahydro-beta-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from L-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.

  DOI：

  10.1021/jm100842v

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
• Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties
  作者：Heba A. Mohamed、Nancy M. R. Girgis、Rainer Wilcken、Matthias R. Bauer、Heather N. Tinsley、Bernard D. Gary、Gary A. Piazza、Frank M. Boeckler、Ashraf H. Abadi

  DOI：10.1021/jm100842v

  日期：2011.1.27

  New derivatives based upon the tetrahydro-beta-carboline-hydantoin and tetrahydro-beta-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from L-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.