5'-adenylic acid, monoanhydride with 2-<5',6'-dideoxy-6'-phosphono-β-D-ribo-hexofuranosyl>-4-thiazolecarboxamide | 102977-54-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: 5'-adenylic acid, monoanhydride with 2-<5',6'-dideoxy-6'-phosphono-β-D-ribo-hexofuranosyl>-4-thiazolecarboxamide
• 英文别名: alpha-methylene-Thiazole-4-carboxamide adenine dinucleotide；[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-[2-[(2R,3S,4R,5R)-5-(4-carbamoyl-1,3-thiazol-2-yl)-3,4-dihydroxyoxolan-2-yl]ethyl]phosphinic acid
• CAS: 102977-54-8
• 化学式: C₂₀H₂₇N₇O₁₃P₂S
• 分子量: 667.487
• InChiKey: PRZRTBJHXQPJGW-HVIRUEHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.5
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  346
• 氢给体数：
  8
• 氢受体数：
  19

反应信息

• 作为产物：
  描述：

  {2-[(3aR,4R,6R,6aR)-6-(4-Carbamoyl-thiazol-2-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethyl}-phosphonic acid dibenzyl ester 在 palladium on activated charcoal 三辛胺 、 氢气 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 40.0~70.0 ℃ 、101.33 kPa 条件下， 反应 21.0h， 生成 5'-adenylic acid, monoanhydride with 2-<5',6'-dideoxy-6'-phosphono-β-D-ribo-hexofuranosyl>-4-thiazolecarboxamide
  参考文献：
  名称：

  Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogs stable to phosphodiesterase hydrolysis

  摘要：

  Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected adenosine 5'-(alpha, beta-methylene)diphosphate with isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against IMP dehydrogenase in vitro. beta-Methylene-TAD (3), the most stable of the TAD phosphonate analogues, produced a depletion of guanine nucleotide pools in an experimentally induced TR-resistant P388 tumor variant that was superior to that obtained with TR in the corresponding sensitive line.

  DOI：

  10.1021/jm00159a027

文献信息

• Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogs stable to phosphodiesterase hydrolysis
  作者：Victor E. Marquez、Christopher K. H. Tseng、Gulilat Gebeyehu、David A. Cooney、Gurpreet S. Ahluwalia、James A. Kelley、Maha Dalal、Richard W. Fuller、Yvonne A. Wilson、David G. Johns

  DOI：10.1021/jm00159a027

  日期：1986.9

  Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected adenosine 5'-(alpha, beta-methylene)diphosphate with isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against IMP dehydrogenase in vitro. beta-Methylene-TAD (3), the most stable of the TAD phosphonate analogues, produced a depletion of guanine nucleotide pools in an experimentally induced TR-resistant P388 tumor variant that was superior to that obtained with TR in the corresponding sensitive line.