6-(1-(2,6-difluoro-phenyl)-propyl)-5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-(1-(2,6-difluoro-phenyl)-propyl)-5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one
• 英文别名: 6-(1-(2,6-difluorophenyl)propyl)-5-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one；6-[1-(2,6-difluorophenyl)propyl]-5-methyl-2-sulfanylidene-1H-pyrimidin-4-one
• 化学式: C₁₄H₁₄F₂N₂OS
• 分子量: 296.341
• InChiKey: IHPWIEIKOULSLC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  73.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(1-(2,6-difluoro-phenyl)-propyl)-5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 、 2-碘丁烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以60%的产率得到SPV122.2
  参考文献：
  名称：

  Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase Inhibitors

  摘要：

  A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F-2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.

  DOI：

  10.1021/jm200734j
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 正丁基锂 、 sodium 、 三乙胺 、 magnesium chloride 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 生成 6-(1-(2,6-difluoro-phenyl)-propyl)-5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one
  参考文献：
  名称：

  Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase Inhibitors

  摘要：

  A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F-2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.

  DOI：

  10.1021/jm200734j

文献信息

• Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase: Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants
  作者：Claudia Mugnaini、Maddalena Alongi、Andrea Togninelli、Harsukh Gevariya、Antonella Brizzi、Fabrizio Manetti、Cesare Bernardini、Lucilla Angeli、Andrea Tafi、Luca Bellucci、Federico Corelli、Silvio Massa、Giovanni Maga、Alberta Samuele、Marcella Facchini、Imma Clotet-Codina、Mercedes Armand-Ugón、José A. Esté、Maurizio Botta

  DOI：10.1021/jm0708230

  日期：2007.12.27

  A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.
• Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3<i>H</i>)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes
  作者：Dante Rotili、Domenico Tarantino、Maxim B. Nawrozkij、Alexandre S. Babushkin、Giorgia Botta、Biagina Marrocco、Roberto Cirilli、Sergio Menta、Roger Badia、Emmanuele Crespan、Flavio Ballante、Rino Ragno、José A. Esté、Giovanni Maga、Antonello Mai

  DOI：10.1021/jm500284x

  日期：2014.6.26

  A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT.
• Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Gianluca Sbardella、Antonello Mai、Sara Bartolini、Sabrina Castellano、Roberto Cirilli、Dante Rotili、Ciro Milite、Marisabella Santoriello、Serena Orlando、Ilaria Sciamanna、Annalucia Serafino、Patrizia Lavia、Corrado Spadafora

  DOI：10.1021/jm200734j

  日期：2011.8.25

  A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F-2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.