S-[[(2Z)-1-(6-aminopurin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2-ylidene)ethyl]-methoxyphosphoryl] ethanethioate | 475598-51-7

• 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: S-[[(2Z)-1-(6-aminopurin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2-ylidene)ethyl]-methoxyphosphoryl] ethanethioate
• CAS: 475598-51-7
• 化学式: C₁₆H₁₈N₅O₇PS
• 分子量: 455.388
• InChiKey: JJWYEBBIUUIKNH-UITAMQMPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  183
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  S-[[(2Z)-1-(6-aminopurin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2-ylidene)ethyl]-methoxyphosphoryl] ethanethioate 在 N-乙酰-L-半胱氨酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.0h， 以90%的产率得到(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：

  (Z)-dimethyl 1-(6-chloro-9H-purin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2(5H)-ylidene)ethylphosphonate 在 ammonium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 7.25h， 生成 S-[[(2Z)-1-(6-aminopurin-9-yl)-2-(3,4-dimethoxy-5-oxofuran-2-ylidene)ethyl]-methoxyphosphoryl] ethanethioate
  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

文献信息

• 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.