(1'R,2'S,4'S,5'S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-[(dibenzylphosphato)methyl]-2-(dibenzyloxyphosphato)bicyclo[3.1.0]hexane | 630103-32-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: (1'R,2'S,4'S,5'S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-[(dibenzylphosphato)methyl]-2-(dibenzyloxyphosphato)bicyclo[3.1.0]hexane
• CAS: 630103-32-1
• 化学式: C₄₀H₄₀ClN₅O₈P₂
• 分子量: 816.187
• InChiKey: OFSJEEPGKPUBGY-GGUWWXLASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.5
• 重原子数：
  56.0
• 可旋转键数：
  18.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  159.14
• 氢给体数：
  1.0
• 氢受体数：
  13.0

反应信息

• 作为反应物：
  描述：

  (1'R,2'S,4'S,5'S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-[(dibenzylphosphato)methyl]-2-(dibenzyloxyphosphato)bicyclo[3.1.0]hexane 在 亚硝酸特丁酯 、 二碘甲烷 作用下， 以 乙腈 为溶剂， 反应 3.0h， 以37%的产率得到(1'R,2'S,4'S,5'S)-4-(6-chloro-2-iodo-9H-purin-9-yl)-1-[(dibenzylphosphato)methyl]-2-(dibenzyloxyphosphato)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation:  Enhanced Potency as P2Y₁ Receptor Antagonists

  摘要：

  Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1), receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1), receptor and by using the radiolabeled antagonist [H-3](2)-chloro-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N-6-methyl-2-iodo analogue 12, which displayed a K-i value in competition for binding of [H-3]5 of 0.79 nM and a K-B value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1), receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(l-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1), receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.

  DOI：

  10.1021/jm030127+
• 作为产物：
  描述：

  (1S,2R,4S,5R)-4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexan-2-ol 在 四氮唑 、 偶氮二甲酸二异丙酯 、 三氯化硼 、 间氯过氧苯甲酸 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 24.0h， 生成 (1'R,2'S,4'S,5'S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-[(dibenzylphosphato)methyl]-2-(dibenzyloxyphosphato)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation:  Enhanced Potency as P2Y₁ Receptor Antagonists

  摘要：

  Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1), receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1), receptor and by using the radiolabeled antagonist [H-3](2)-chloro-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N-6-methyl-2-iodo analogue 12, which displayed a K-i value in competition for binding of [H-3]5 of 0.79 nM and a K-B value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1), receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(l-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1), receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.

  DOI：

  10.1021/jm030127+