2-Methyl-5-[[4-methylidene-5-oxo-2-(4-phenylphenyl)oxolan-2-yl]methoxy]pyrazole-3-carboxylic acid | 692259-29-3

• 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: 2-Methyl-5-[[4-methylidene-5-oxo-2-(4-phenylphenyl)oxolan-2-yl]methoxy]pyrazole-3-carboxylic acid
• CAS: 692259-29-3
• 化学式: C₂₃H₂₀N₂O₅
• 分子量: 404.422
• InChiKey: HFEFAVJHQKQYHO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  90.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-amino-N-(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-pyrrole-2-carboxamide dihydrochloride 、 2-Methyl-5-[[4-methylidene-5-oxo-2-(4-phenylphenyl)oxolan-2-yl]methoxy]pyrazole-3-carboxylic acid 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-3-[2-biphenyl-4-yl-4-methylene-5-oxotetrahydrofuran-2-ylmethoxy]-1H-pyrazole-5-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Hybrid Molecules Containing α-Methylene-γ-butyrolactones and Polypyrrole Minor Groove Binders

  摘要：

  We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a critical role in chromatin architecture and DNA metabolism.

  DOI：

  10.1021/jm031104y
• 作为产物：
  描述：

  2-溴-4-苯基乙酰苯 在 lithium hydroxide 、 苄基三乙基氯化铵 、 sodium hydride 、 potassium carbonate 、 对苯二酚 、 三氟乙酸 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 71.5h， 生成 2-Methyl-5-[[4-methylidene-5-oxo-2-(4-phenylphenyl)oxolan-2-yl]methoxy]pyrazole-3-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Hybrid Molecules Containing α-Methylene-γ-butyrolactones and Polypyrrole Minor Groove Binders

  摘要：

  We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a critical role in chromatin architecture and DNA metabolism.

  DOI：

  10.1021/jm031104y

文献信息

• Design, Synthesis, and Biological Evaluation of Hybrid Molecules Containing α-Methylene-γ-Butyrolactones and α-Bromoacryloyl Moieties
  作者：Romeo Romagnoli、Pier Giovanni Baraldi、Mojgan Aghazadeh Tabrizi、Jaime Bermejo、Francisco Estévez、Monica Borgatti、Roberto Gambari

  DOI：10.1021/jm058012o

  日期：2005.12.1

  The synthesis and biological activity of hybrids 8-18 prepared combining alpha-methylene-gamma-butyrolactones and alpha-bromoacryloylamides have been described and their structure -activity relationships discussed. All these heterobifunctional compounds demonstrate good antileukemic activity, significantly superior to that of both alkylating units alone. Using the human leukemia HL-60 cell line, selected compounds 10, 11, 13, and 17 were found to induce morphological changes and internucleosomal DNA fragmentation characteristic of apoptotic cell death.
• Design, Synthesis, and Biological Evaluation of Hybrid Molecules Containing α-Methylene-γ-butyrolactones and Polypyrrole Minor Groove Binders
  作者：Pier Giovanni Baraldi、Maria del Carmen Nunez、Mojgan Aghazadeh Tabrizi、Erik De Clercq、Jan Balzarini、Jaime Bermejo、Francisco Estévez、Romeo Romagnoli

  DOI：10.1021/jm031104y

  日期：2004.5.1

  We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a critical role in chromatin architecture and DNA metabolism.