8-(4-(hydroxymethyl)phenyl)-2-morpholino-4H-chromen-4-one | 503468-78-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-(4-(hydroxymethyl)phenyl)-2-morpholino-4H-chromen-4-one
• 英文别名: 8-(4-Hydroxymethylphenyl)-2-morpholin-4-ylchromen-4-one；8-[4-(hydroxymethyl)phenyl]-2-morpholin-4-ylchromen-4-one
• CAS: 503468-78-8
• 化学式: C₂₀H₁₉NO₄
• 分子量: 337.375
• InChiKey: GQVASXBFAOLNLS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-(4-(hydroxymethyl)phenyl)-2-morpholino-4H-chromen-4-one 在 4-二甲氨基吡啶 、 对甲苯磺酸 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 65.0h， 生成 4-(2-morpholino-4-oxo-4H-chromen-8-yl)benzyl 2-amino-4-methylpentanoate
  参考文献：
  名称：

  Synthesis and Characterization of a Novel Prostate Cancer-Targeted Phosphatidylinositol-3-kinase Inhibitor Prodrug

  摘要：

  The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer-specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH2-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH2-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound.

  DOI：

  10.1021/jm300881a
• 作为产物：
  描述：

  4-乙酰基吗啉 在 四(三苯基膦)钯 、 三氟甲磺酸酐 、 potassium carbonate 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 二氯甲烷 为溶剂， 反应 96.0h， 生成 8-(4-(hydroxymethyl)phenyl)-2-morpholino-4H-chromen-4-one
  参考文献：
  名称：

  Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach

  摘要：

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

  DOI：

  10.1021/jm050444b

文献信息

• Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries
  作者：Justin J.J. Leahy、Bernard T. Golding、Roger J. Griffin、Ian R. Hardcastle、Caroline Richardson、Laurent Rigoreau、Graeme C.M. Smith

  DOI：10.1016/j.bmcl.2004.09.060

  日期：2004.12

  A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries. which were screened as inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a highly potent and selective DNA-PK inhibitor (IC50 = 14nM), exhibiting ATP-competitive inhibition kinetics. (C) 2004 Elsevier Ltd. All rights reserved.
• Compositions and Methods for Inducing Apoptosis in Prostate Cancer Cells
  申请人：Kulik George

  公开号：US20120237533A1

  公开（公告）日：2012-09-20

  Compositions and methods for inhibiting the growth of cancer cells, particularly prostate cancer cells are disclosed.
• [EN] PROSTATE CANCER TARGETED PRODRUGS AND METHODS OF USE THEREOF<br/>[FR] PROMÉDICAMENTS DIRIGÉS CONTRE LE CANCER DE LA PROSTATE ET LEURS MÉTHODES D'UTILISATION
  申请人：UNIV WAKE FOREST HEALTH SCIENCES

  公开号：WO2014012093A1

  公开（公告）日：2014-01-16

  Compositions and methods for inhibiting the growth of cancer cells, particularly prostate cancer cells, are disclosed. This invention relates to the fields of oncology and modulation of signal transduction pathways for inducing targeted cell death. Prodrugs for the treatment of cancer, particularly prostate cancer, are provided. The prodrugs comprise a phosphatidylinositol-3-kinase (PI3K) inhibitor linked to a prostate specific antigen (PSA) cleavable peptide.
• Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach
  作者：Ian R. Hardcastle、Xiaoling Cockcroft、Nicola J. Curtin、Marine Desage El-Murr、Justin J. J. Leahy、Martin Stockley、Bernard T. Golding、Laurent Rigoreau、Caroline Richardson、Graeme C. M. Smith、Roger J. Griffin

  DOI：10.1021/jm050444b

  日期：2005.12.1

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 3238}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 3226}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 3238} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.
• Synthesis and Characterization of a Novel Prostate Cancer-Targeted Phosphatidylinositol-3-kinase Inhibitor Prodrug
  作者：Daniele Baiz、Tanya A. Pinder、Sazzad Hassan、Yelena Karpova、Freddie Salsbury、Mark E. Welker、George Kulik

  DOI：10.1021/jm300881a

  日期：2012.9.27

  The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer-specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH2-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH2-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound.