(1'R,2'S,4'S,5'S)-phosphoric acid di-tert-butyl ester 1-(di-tert-butoxyphosphoryloxymethyl)-4-(2-iodo-6-methylaminopurin-9-yl)bicyclo[3.1.0]hex-2-yl ester | 630103-46-7

• 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)-phosphoric acid di-tert-butyl ester 1-(di-tert-butoxyphosphoryloxymethyl)-4-(2-iodo-6-methylaminopurin-9-yl)bicyclo[3.1.0]hex-2-yl ester
• CAS: 630103-46-7
• 化学式: C₂₉H₅₀IN₅O₈P₂
• 分子量: 785.597
• InChiKey: YZECRGKNPYXBEF-SJUQETRFSA-N

物化性质

• 沸点：
  757.1±70.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.3
• 重原子数：
  45.0
• 可旋转键数：
  11.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  145.15
• 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)-phosphoric acid di-tert-butyl ester 1-(di-tert-butoxyphosphoryloxymethyl)-4-(2-iodo-6-methylaminopurin-9-yl)bicyclo[3.1.0]hex-2-yl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (1'R,2'S,4'S,5'S)-4-(2-iodo-6-methylamino-9H-purin-9-yl)-1-[(phosphato)methyl]-2-(phosphato)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：

  在 甲醇 、 potassium carbonate 、 间氯过氧苯甲酸 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 4.5h， 生成 (1'R,2'S,4'S,5'S)-phosphoric acid di-tert-butyl ester 1-(di-tert-butoxyphosphoryloxymethyl)-4-(2-iodo-6-methylaminopurin-9-yl)bicyclo[3.1.0]hex-2-yl ester
  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+

文献信息

• Functionalized Congeners of P2Y₁ Receptor Antagonists: 2-Alkynyl (<i>N</i>)-Methanocarba 2′-Deoxyadenosine 3′,5′-Bisphosphate Analogues and Conjugation to a Polyamidoamine (PAMAM) Dendrimer Carrier
  作者：Sonia de Castro、Hiroshi Maruoka、Kunlun Hong、S. Michael Kilbey、Stefano Costanzi、Béatrice Hechler、Garth G. Brown, Jr.、Christian Gachet、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/bc900569u

  日期：2010.7.21

  is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of the P2Y1 receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′

  P2Y 1受体是一种由 ADP 激活的促血栓形成 G 蛋白偶联受体 (GPCR)。P2Y 1受体的腺嘌呤核苷酸 3',5'-二磷酸拮抗剂的核糖部分的北 (N) 环构象的偏好是通过使用环约束的甲烷卡巴（双环 [3.1.0] 己烷）环作为一种核糖替代品。设计了一系列可共价连接的N 6 -甲基-( N )-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates 包含延伸的 2-炔基链，并与人 (h) P2Y 1 的结合亲和力受体确定。这些功能化同类物的链包含亲水部分、反应性取代基或生物素，通过酰胺连接。中间酰胺基团的链长和位置的变化揭示了羧基同源物8 ( K i 23 nM) 和扩展胺同源物15 ( K i 132 nM) 的高亲和力，两者都具有 2-(1-戊炔酰基) 基团。含有延长的 ε-氨基己酰基间隔链的生物素缀合物18表现出比较短的生物素化类似物更高的亲和力。或者，同源