phaeosphaeride A | 1403754-53-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: phaeosphaeride A
• 英文别名: (2S,3S,4S)-3,4-dihydroxy-6-methoxy-3-methyl-7-methylidene-2-pentyl-2,4-dihydropyrano[2,3-c]pyrrol-5-one
• CAS: 1403754-53-9
• 化学式: C₁₅H₂₃NO₅
• 分子量: 297.351
• InChiKey: PQXBZFLVJGBOAD-VZJVUDMVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  79.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phaeosphaeride A 在 sodium acetate 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 12.5h， 生成 (2S,3S,4R)-3,4-dihydroxy-6-methoxy-3-methyl-7-methylidene-2-pentyl-2,4-dihydropyrano[2,3-c]pyrrol-5-one
  参考文献：
  名称：

  Synthetic and Biological Studies of Phaeosphaerides

  摘要：

  The signal transducer and activator of transcription 3 (STAT3) has been validated as a suitable target for cancer therapy. Recent evidence by our group and others has shown that phaeosphaerides act as inhibitors of the STAT3 pathway. An efficient synthetic sequence to phaeosphaeride la has been previously disclosed. In this work, the first total synthesis of (+/-)-phaeosphaeride B (1d) and the unnatural phaeosphaeride 1b is reported. Additionally, the biological activities of la and 1b were investigated. (6S,7S,8S)-1a and (6R,7S,8S)-1b inhibited granulocyte colony-stimulating factor (GCSF)-stimulated phosphorylation of STAT1, STAT3, and STAT5 and IL-6-stimulated nuclear translocation of STAT3 alpha. In an SPR-based assay, (6S,7S,8S)-1a and (6R,7S,8S)-1b showed minimal ability to inhibit binding of STAT3 to its immobilized phosphotyrosylpeptide ligand (IC50 > 100 mu M). Thus, (6S,7S,8S)-1a and (6R,7S,8S)-1b are likely upstream inhibitors of a kinase in the STAT signaling pathway and do not act through the inhibition of STAT3 dimerization by the blocking of the SH2 binding domain.

  DOI：

  10.1021/jo500545d
• 作为产物：
  描述：

  3-(hydroxy-2,2,4-(trimethyl-5-pentyl-1,3-dioxolan-4-yl)-methyl)-4-methoxy-5-methylenefuran-2(5H)-one 在 四丁基氟化铵 、 对甲苯磺酸 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 15.67h， 生成 phaeosphaeride A
  参考文献：
  名称：

  Total Synthesis and Biological Activity of the Proposed Structure of Phaeosphaeride A

  摘要：

  The total synthesis of the structure assigned to the natural product phaeosphaeride A la was accomplished. The key steps involve the addition of vinyllithium reagent 7 to the acetonide-protected aldehyde 8 to access the carbon backbone of la, the introduction of the methoxylamino group followed by intramolecular hetero-Michael cyclization, and methanol elimination to form the dihydropyran ring. In this study, both enantiomers of la were synthesized and tested for biological activity. Preliminary results showed that (6R,7R,8R)-1a and (6S,7S,8S)-1a inhibit STAT3-dependent transcriptional activity in a dose-dependent manner and exhibit antiproliferative properties in breast (MDA-MB-231) and pancreatic (PANC-1) cancer cells.

  DOI：

  10.1021/jo301662e

文献信息

• Phaeosphaeride A, an Inhibitor of STAT3-Dependent Signaling Isolated from an Endophytic Fungus
  作者：Katherine N. Maloney、Wenshan Hao、Jun Xu、Jay Gibbons、John Hucul、Deborah Roll、Sean F. Brady、Frank C. Schroeder、Jon Clardy

  DOI：10.1021/ol061556f

  日期：2006.8.1

  Phaeosphaeride A, a nitrogen-containing bicyclic compound produced by an endophytic fungus, inhibits signaling by the transcription factor STAT3.
• Total Synthesis and Biological Activity of the Proposed Structure of Phaeosphaeride A
  作者：Anthoula Chatzimpaloglou、Maria P. Yavropoulou、Karien E. Rooij、Ralf Biedermann、Uwe Mueller、Stefan Kaskel、Vasiliki Sarli

  DOI：10.1021/jo301662e

  日期：2012.11.2

  The total synthesis of the structure assigned to the natural product phaeosphaeride A la was accomplished. The key steps involve the addition of vinyllithium reagent 7 to the acetonide-protected aldehyde 8 to access the carbon backbone of la, the introduction of the methoxylamino group followed by intramolecular hetero-Michael cyclization, and methanol elimination to form the dihydropyran ring. In this study, both enantiomers of la were synthesized and tested for biological activity. Preliminary results showed that (6R,7R,8R)-1a and (6S,7S,8S)-1a inhibit STAT3-dependent transcriptional activity in a dose-dependent manner and exhibit antiproliferative properties in breast (MDA-MB-231) and pancreatic (PANC-1) cancer cells.
• Synthetic and Biological Studies of Phaeosphaerides
  作者：Anthoula Chatzimpaloglou、Mikhail Kolosov、T. Kris Eckols、David J. Tweardy、Vasiliki Sarli

  DOI：10.1021/jo500545d

  日期：2014.5.2

  The signal transducer and activator of transcription 3 (STAT3) has been validated as a suitable target for cancer therapy. Recent evidence by our group and others has shown that phaeosphaerides act as inhibitors of the STAT3 pathway. An efficient synthetic sequence to phaeosphaeride la has been previously disclosed. In this work, the first total synthesis of (+/-)-phaeosphaeride B (1d) and the unnatural phaeosphaeride 1b is reported. Additionally, the biological activities of la and 1b were investigated. (6S,7S,8S)-1a and (6R,7S,8S)-1b inhibited granulocyte colony-stimulating factor (GCSF)-stimulated phosphorylation of STAT1, STAT3, and STAT5 and IL-6-stimulated nuclear translocation of STAT3 alpha. In an SPR-based assay, (6S,7S,8S)-1a and (6R,7S,8S)-1b showed minimal ability to inhibit binding of STAT3 to its immobilized phosphotyrosylpeptide ligand (IC50 > 100 mu M). Thus, (6S,7S,8S)-1a and (6R,7S,8S)-1b are likely upstream inhibitors of a kinase in the STAT signaling pathway and do not act through the inhibition of STAT3 dimerization by the blocking of the SH2 binding domain.