adenosine 5'- 5'<*>5'-ester with 2-β-D-ribofuranosyl-4-thiazolecarboxamide | 102977-57-1

• 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: adenosine 5'- 5'<*>5'-ester with 2-β-D-ribofuranosyl-4-thiazolecarboxamide
• 英文别名: P¹-(thiazofurin-5-'-yl)-P²-(adenosin-5'-yl)methylenebis(phosphonate)；P¹-tiazofurin P²-adenosine-5'-methylenebisphosphonate；adenosine 5'-[hydrogen(phosphonomethyl)phosphonate] 5'[*]5'-ester with 2-β-D-ribofuranosyl-4-thiazolecarboxamide；beta-Methylene-thiazole-4-carboxyamide-adenine dinucleotide；[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-[[[(2R,3S,4R,5R)-5-(4-carbamoyl-1,3-thiazol-2-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methyl]phosphinic acid
• CAS: 102977-57-1
• 化学式: C₂₀H₂₇N₇O₁₃P₂S
• 分子量: 667.487
• InChiKey: CRWWKLKZKYLFQV-HVIRUEHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -6
• 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-[2,3-O-(1-甲基乙亚基)-beta-D-呋喃核糖基]-4-噻唑甲酰胺 在 吡啶 、 Dowex 50-X₈ 、 水 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 反应 20.0h， 生成 adenosine 5'- 5'<*>5'-ester with 2-β-D-ribofuranosyl-4-thiazolecarboxamide
  参考文献：
  名称：

  The Practical Synthesis of a Methylenebisphosphonate Analogue of Benzamide Adenine Dinucleotide:  Inhibition of Human Inosine Monophosphate Dehydrogenase (Type I and II)

  摘要：

  beta-Methylene-BAD (8), a nonhydrolyzable analogue of benzamide adenine dinucleotide (BAD), was synthesized as potential inhibitor of human inosine monophosphate dehydrogenase (IMPDH). Treatment of 2',3'-O-isopropylideneadenosine 5'-methylenebisphosphonate (15) with DCC afforded P-1,P-4-bis(2',3'-O-isopropylideneadenosine) 5'-P-1,P-2:P-3,P-4-dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2',3'-O-isopropylidene-beta-D-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired beta-methylene-BAD (8) in 95% yield. In a similar manner, treatment of 18 with 2',3'-O-isopropylidenetiazofurin (21) followed by hydrolysis and deprotection afforded beta-methylene-TAD (5) in 91% yield. Compound 8 (IC50 = 0.665 mu M) was found to be a 6-8 times less potent inhibitor of IMPDH than 5 (IC50 = 0.107 mu M) and was almost equally potent against IMPDH type I and type II. Although TAD and beta-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (K-i = 333 mu M) was found to be 50-fold lower than that of the parent pyrophosphate 7 (K-i = 6.3 mu M).

  DOI：

  10.1021/jm960641y

文献信息

• Efficient Synthesis of Methylenebis(phosphonate) Analogues of P¹,P²-Disubstituted Pyrophosphates of Biological Interest. A Novel Plausible Mechanism
  作者：Krzysztof W. Pankiewicz、Krystyna Lesiak、Kyoichi A. Watanabe

  DOI：10.1021/ja964058i

  日期：1997.4.1

  Synthesis of novel nucleoside bicyclic trisanhydrides 7 in the reaction of nucleoside-5'-methylenebis-(phosphonate)s (4) with DCC is described. They were obtained by P-1,P-3- and P-2,P-3-dehydration of initially formed P-1,P-2,P-3,P-4-bismethylenetetraphosphonate 6. Reaction of 7 (N = 2',3'-O-isopropylideneadenosin-5'-yl) with 2',3'-O-isopropylidenetiazofurin gave, after hydrolysis and deisopropylidenation, beta-methylene-TAD (10a), the known potent inhibitor of inosine monophosphate dehydrogenase (IMPDH). Similar reaction of 7 with benzyl 2,3-O-isopropylidene-beta-D-riboside followed by hydrolysis and deprotection afforded a new methylenebis(phosphonate) analogue of ADP-ribose 10b. Upon reaction of 7 with riboflavin, the corresponding beta-methylene-FAD (10c) was obtained. Bicyclic trisanhydride 7 prepared from (2',3'-O-isopropylidene-N-4-acetylcytidin-5'yl)methylenebis(phosphonate) was used in the synthesis of the methylenebis(phosphonate) analogues of CDP-ethanolamine 10d and CDP-dipalmitoylglycerol 10e.
• 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.
• The Practical Synthesis of a Methylenebisphosphonate Analogue of Benzamide Adenine Dinucleotide:  Inhibition of Human Inosine Monophosphate Dehydrogenase (Type I and II)
  作者：Krzysztof W. Pankiewicz、Krystyna Lesiak、Andrzej Zatorski、Barry M. Goldstein、Stephen F. Carr、Marek Sochacki、Alokes Majumdar、Michael Seidman、Kyoichi A. Watanabe

  DOI：10.1021/jm960641y

  日期：1997.4.1

  beta-Methylene-BAD (8), a nonhydrolyzable analogue of benzamide adenine dinucleotide (BAD), was synthesized as potential inhibitor of human inosine monophosphate dehydrogenase (IMPDH). Treatment of 2',3'-O-isopropylideneadenosine 5'-methylenebisphosphonate (15) with DCC afforded P-1,P-4-bis(2',3'-O-isopropylideneadenosine) 5'-P-1,P-2:P-3,P-4-dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2',3'-O-isopropylidene-beta-D-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired beta-methylene-BAD (8) in 95% yield. In a similar manner, treatment of 18 with 2',3'-O-isopropylidenetiazofurin (21) followed by hydrolysis and deprotection afforded beta-methylene-TAD (5) in 91% yield. Compound 8 (IC50 = 0.665 mu M) was found to be a 6-8 times less potent inhibitor of IMPDH than 5 (IC50 = 0.107 mu M) and was almost equally potent against IMPDH type I and type II. Although TAD and beta-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (K-i = 333 mu M) was found to be 50-fold lower than that of the parent pyrophosphate 7 (K-i = 6.3 mu M).