(Z)-dimethyl 1-(6-chloro-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphonate | 347364-29-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (Z)-dimethyl 1-(6-chloro-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphonate
• 英文别名: (5Z)-5-[2-(6-chloropurin-9-yl)-2-dimethoxyphosphoryl-ethylidene]-3,4-dimethoxy-furan-2-one；(5Z)-5-[2-(6-chloropurin-9-yl)-2-dimethoxyphosphorylethylidene]-3,4-dimethoxyfuran-2-one
• CAS: 347364-29-8
• 化学式: C₁₅H₁₆ClN₄O₇P
• 分子量: 430.741
• InChiKey: KMHTYHHUTHPWPP-YVMONPNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  124
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (Z)-dimethyl 1-(6-chloro-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphonate 在 ammonium hydroxide 、 N-乙酰-L-半胱氨酸 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 8.25h， 生成 (Z)-O-methyl O-hydrogen 1-(6-amino-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphothioate
  参考文献：
  名称：

  Reactions of purines-containing butenolides with l-cysteine or N-acetyl-l-cysteine as model biological nucleophiles: a potent mechanism-based inhibitor of ribonucleotide reductase caused apoptosis in breast carcinoma MCF7 cells

  摘要：

  Thiols are the most reactive nucleophilic reagents among the biological models investigated. The reactivity of butenolides la-c, 2-4, and 6 8 toward L-cysteine, a model biological nucleophile, was studied spectrophotometrically. The rates of the reactions were measured and correlated with antitumour activity of these molecules. N-Acetylcysteine addition product 5, resulting from the treatment of butenolide 4 with glutathione precursor, N-acetyl-L-cysteine, was isolated. Unlike purine-containing gamma-(Z)-ethylidene-2,3-dimethoxybutenolides la-c, 4, 6, and 7, adduct 5 and butenolides 10-12 did not exhibit inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. As such, the biological activity of purine-containing butenolides can be attributed to their adenine moiety as a recognition site as well as their reactivity towards the cysteine residues of functional proteins forming covalent bond via reverse Michael type addition. Adenine-containing phosphonothioanhydride derivative 8 was also synthesised. Its reaction with N-acetyl-L-cysteine produced N,S-diacetylcysteine and thiophosphonate 9. Compound 9 did not exhibit anticancer activity; yet its precursor 8 displayed the most pronounced inhibition on all the examined malignant tumour cell lines. In the presence Of L-cysteine, cytotoxicity of 4 and 8 was decreased, whereas glutathione addition more influenced on the cytotoxicity of 8. It was found that adenine-containing phosphonothioanhydride 8 functions as a significant irreversible inactivator of the Escherichia coli ribonucleoside diphosphate reductase. After treatment of MCF7 cells with compound 8, fluorescence microscopy demonstrated the presence of nucleus shrinkage or segmentation. This apoptotic morphology, however, was not pronounced in the presence of glutathione or dithiotheritol. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.

  DOI：

  10.1016/s0223-5234(02)01333-8
• 作为产物：
  描述：

  2,3-O-dimethyl-5,6-di-O-p-toluenesulphonyl-L-ascorbic acid 在 三氟甲烷磺酰氯 、 四丁基氯化铵 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 30.5h， 生成 (Z)-dimethyl 1-(6-chloro-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphonate
  参考文献：
  名称：

  含嘌呤的丁烯内酯的合成和生物学评估。

  摘要：

  γ-（Z）-亚乙基-2,3-二甲氧基丁烯化物3a，γ-（Z）-亚乙基-2-甲氧基-3-（4-硝基）苄氧基丁烯化物3b，γ-（Z）-亚乙基-6-氯嘌呤衍生物2-（4-硝基）苄氧基-3-甲氧基丁烯化物3c，γ-（Z）-亚乙基-2,3-二（4-硝基）苄氧基丁烯化物3d和二甲基膦酰基-γ-（Z）-亚乙基-2,3-合成了二甲氧基丁烯内酯11以及γ-（Z）-亚乙基-2，3-二甲氧基丁烯内酯6的腺嘌呤衍生物。6的高产率合成中的关键步骤涉及前体3a中C（4）= C（5）的水合/脱水。在升高的NH 4 OH存在下，将3a与水进行反向迈克尔型加成以产生水合物5。在37℃下，在S-腺苷-L-高半胱氨酸水解酶的存在下也将6水合以得到5。图6显示出对该酶的抑制性质。这种类型的II（跨C（4）= C（5）的酶介导的水添加）机制是S-腺苷-L-高半胱氨酸水解酶“酶-底物中间体”失活的第一个例子。与基于I型机制的失活相反

  DOI：

  10.1021/jm0004446

文献信息

• Design, synthesis, and anticancer activity of phosphonic acid diphosphate derivative of adenine-containing butenolide and its water-soluble derivatives of paclitaxel with high antitumor activity
  作者：Ali A Moosavi-Movahedi、Shahram Hakimelahi、Jamshid Chamani、Ghadam Ali Khodarahmi、Farshid Hassanzadeh、Fen-Tair Luo、Tai Wei Ly、Kak-Shan Shia、Chi-Feng Yen、Moti L Jain、Ramasamy Kulatheeswaran、Cuihua Xue、Manijeh Pasdar、Gholam Hossein Hakimelahi

  DOI：10.1016/s0968-0896(03)00524-8

  日期：2003.10

  Synthesis of adenine derivative of triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 4 was accomplished by treatment of phosphonate 3 with 5-phosphoribosyl I-pyrophosphate in the presence of 5-phosphoribosyl I-pyrophosphate synthetase. It was found that triphosphonate 4 functions as an irreversible stoichiometric inactivator of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). Triphosphonate 4 exhibited potent inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. Paclitaxel ester derivatives of adenine-containing triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 8-10 were also synthesized. Like triphosphonate 4, compound 8 exhibited inhibitory property toward RDPR. It also induced microtubule assembly similar to paclitaxel (5). The structure of the chlorodiester linker in 8 was found to account for this dual property. After treatment of MCF7 cells with compounds 4, 5, and 8, fluorescence microscope examination demonstrated the presence of nucleus shrinkage or segmentation. Bifunctional prodrug 8 exhibited higher lipophilicity than 4 and higher water-solubility than 5. Pro-dual-drug 8 exhibited more pronounced anticancer activity relative to that of the triphosphonate 4 and paclitaxel (5). In contrast, compound 9, resulting from the linkage of triphosphonate 4 and paclitaxel (5) through a diester unit, was only found to function as a highly water-soluble prodrug for paclitaxel (5). It induced microtubule assembly in vitro, but did not show inhibitory property toward RDPR. On the other hand, compound 10, an aggregate of triphosphonate 4 and paclitaxel (5), neither functioned as an inhibitor of RDPR nor exhibited microtubule assembly stimulating activity in vitro. (C) 2003 Elsevier Ltd. All rights reserved.
• Synthesis and Biological Evaluation of Purine-Containing Butenolides
  作者：Gholam H. Hakimelahi、Nai-Wen Mei、Ali A. Moosavi-Movahedi、Hady Davari、Shahram Hakimelahi、Ke-Yung King、Jih Ru Hwu、Yuh-Sheng Wen

  DOI：10.1021/jm0004446

  日期：2001.5.1

  crystallographic analysis. For the synthesis of phosphonate derivative 11, the key step involved chlorination of phosphonate 9 by use of CF3SO2Cl and 1,8-diazabicyclo[5.4.0]undec-7-ene in CH2Cl2. 6-Chloropurine-containing butenolide 3d, 6-chloropurine derivative of 4-hydroxybutenolide 4, and adenine-containing 4-hydroxybutenolide 5 did not show anticancer and antiviral activities. 6-Chloropurine-containing

  γ-（Z）-亚乙基-2,3-二甲氧基丁烯化物3a，γ-（Z）-亚乙基-2-甲氧基-3-（4-硝基）苄氧基丁烯化物3b，γ-（Z）-亚乙基-6-氯嘌呤衍生物2-（4-硝基）苄氧基-3-甲氧基丁烯化物3c，γ-（Z）-亚乙基-2,3-二（4-硝基）苄氧基丁烯化物3d和二甲基膦酰基-γ-（Z）-亚乙基-2,3-合成了二甲氧基丁烯内酯11以及γ-（Z）-亚乙基-2，3-二甲氧基丁烯内酯6的腺嘌呤衍生物。6的高产率合成中的关键步骤涉及前体3a中C（4）= C（5）的水合/脱水。在升高的NH 4 OH存在下，将3a与水进行反向迈克尔型加成以产生水合物5。在37℃下，在S-腺苷-L-高半胱氨酸水解酶的存在下也将6水合以得到5。图6显示出对该酶的抑制性质。这种类型的II（跨C（4）= C（5）的酶介导的水添加）机制是S-腺苷-L-高半胱氨酸水解酶“酶-底物中间体”失活的第一个例子。与基于I型机制的失活相反
• Reactions of purines-containing butenolides with l-cysteine or N-acetyl-l-cysteine as model biological nucleophiles: a potent mechanism-based inhibitor of ribonucleotide reductase caused apoptosis in breast carcinoma MCF7 cells
  作者：Gholam Hossein Hakimelahi、Ali A Moosavi-Movahedi、Thota Sambaiah、Jia-Liang Zhu、Krishna S Ethiraj、Manijeh Pasdar、Shahram Hakimelahi

  DOI：10.1016/s0223-5234(02)01333-8

  日期：2002.3

  Thiols are the most reactive nucleophilic reagents among the biological models investigated. The reactivity of butenolides la-c, 2-4, and 6 8 toward L-cysteine, a model biological nucleophile, was studied spectrophotometrically. The rates of the reactions were measured and correlated with antitumour activity of these molecules. N-Acetylcysteine addition product 5, resulting from the treatment of butenolide 4 with glutathione precursor, N-acetyl-L-cysteine, was isolated. Unlike purine-containing gamma-(Z)-ethylidene-2,3-dimethoxybutenolides la-c, 4, 6, and 7, adduct 5 and butenolides 10-12 did not exhibit inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. As such, the biological activity of purine-containing butenolides can be attributed to their adenine moiety as a recognition site as well as their reactivity towards the cysteine residues of functional proteins forming covalent bond via reverse Michael type addition. Adenine-containing phosphonothioanhydride derivative 8 was also synthesised. Its reaction with N-acetyl-L-cysteine produced N,S-diacetylcysteine and thiophosphonate 9. Compound 9 did not exhibit anticancer activity; yet its precursor 8 displayed the most pronounced inhibition on all the examined malignant tumour cell lines. In the presence Of L-cysteine, cytotoxicity of 4 and 8 was decreased, whereas glutathione addition more influenced on the cytotoxicity of 8. It was found that adenine-containing phosphonothioanhydride 8 functions as a significant irreversible inactivator of the Escherichia coli ribonucleoside diphosphate reductase. After treatment of MCF7 cells with compound 8, fluorescence microscopy demonstrated the presence of nucleus shrinkage or segmentation. This apoptotic morphology, however, was not pronounced in the presence of glutathione or dithiotheritol. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.