(1'R,2'R,3'S,4'R,5'S)-4-(2,6-dichloropurin-9-yl)-1-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) | 281191-63-7

• 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: (1'R,2'R,3'S,4'R,5'S)-4-(2,6-dichloropurin-9-yl)-1-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
• 英文别名: 2,6-dichloro-9-[(1R,2R,4S,5R,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]purine
• CAS: 281191-63-7
• 化学式: C₂₂H₂₂Cl₂N₄O₃
• 分子量: 461.348
• InChiKey: MJBJZCQVFXFYEV-UOCLLMPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  71.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1'R,2'R,3'S,4'R,5'S)-4-(2,6-dichloropurin-9-yl)-1-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) 在 三氯化硼 、 邻苯二甲酸二甲酯 、 对甲苯磺酸 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 生成 (1R,2R,3S,4R,5S)-4-(2,6-dichloropurin-9-yl)-1-hydroxymethyl-2,3-O-isopropylidenebicyclo[3.1.0]hexane
  参考文献：
  名称：

  Ring-Constrained (N)-Methanocarba nucleosides as adenosine receptor agonists: independent 5′-Uronamide and 2′-deoxy modifications

  摘要：

  Novel methanocarba adenosine analogues, having the pseudo-ribose northern (N) conformation preferred at adenosine receptors (ARs), were synthesized and tested in binding assays. The 5'-uronamide modification preserved [N-6-(3-iodobenzyl)] or enhanced (N-6-methyl) affinity at A(3)ARs, while the 2'-deoxy modification reduced affinity and efficacy in a functional assay. Published by Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(01)00213-x
• 作为产物：
  描述：

  2,6-二氯嘌呤 、 (1R,2R,4S,5S,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol 在 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 6.0h， 以70%的产率得到(1'R,2'R,3'S,4'R,5'S)-4-(2,6-dichloropurin-9-yl)-1-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
  参考文献：
  名称：

  嘌呤核苷的甲烷卡巴类似物作为有效和选择性的腺苷受体激动剂。

  摘要：

  腺苷受体激动剂具有心脏保护、脑保护和抗炎特性。我们报告核糖部分纳入环约束的碳环修饰是设计具有良好药效学特性的 A(1) 和 A(3) 受体激动剂的一般方法。虽然腺苷激动剂的简单碳环取代大大降低了效力，但甲卡巴-腺苷类似物现在已经确定了糖褶皱在稳定活性腺苷受体结合构象中的作用，从而可以识别出一种有利的异构体。在此类类似物中，稠合环丙烷部分将核苷的假糖环限制为北（N）或南（S）构象，如假旋转循环中所定义。在 A(1)、A(2A) 和 A(3) 受体的结合试验中，(N)-methanocarba-腺苷比 (S)-类似物具有更高的亲和力，特别是在人类 A(3) 受体上（N/S 亲和力比为 150）。(N)-Methanocarba 类似物的各种 N(6)-取代的腺苷衍生物，包括环戊基和 3-碘苄基，其中母体化合物分别是 A(1) 或 A(3) 受体的有效激动剂，被合成。N(6)-环戊基衍生物对 A(1)

  DOI：

  10.1021/jm9905965

文献信息

• Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists
  作者：Kenneth A. Jacobson、Xiao-duo Ji、An-Hu Li、Neli Melman、Maqbool A. Siddiqui、Kye-Jung Shin、Victor E. Marquez、R. Gnana Ravi

  DOI：10.1021/jm9905965

  日期：2000.6.1

  (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding

  腺苷受体激动剂具有心脏保护、脑保护和抗炎特性。我们报告核糖部分纳入环约束的碳环修饰是设计具有良好药效学特性的 A(1) 和 A(3) 受体激动剂的一般方法。虽然腺苷激动剂的简单碳环取代大大降低了效力，但甲卡巴-腺苷类似物现在已经确定了糖褶皱在稳定活性腺苷受体结合构象中的作用，从而可以识别出一种有利的异构体。在此类类似物中，稠合环丙烷部分将核苷的假糖环限制为北（N）或南（S）构象，如假旋转循环中所定义。在 A(1)、A(2A) 和 A(3) 受体的结合试验中，(N)-methanocarba-腺苷比 (S)-类似物具有更高的亲和力，特别是在人类 A(3) 受体上（N/S 亲和力比为 150）。(N)-Methanocarba 类似物的各种 N(6)-取代的腺苷衍生物，包括环戊基和 3-碘苄基，其中母体化合物分别是 A(1) 或 A(3) 受体的有效激动剂，被合成。N(6)-环戊基衍生物对 A(1)
• Ring-Constrained (N)-Methanocarba nucleosides as adenosine receptor agonists: independent 5′-Uronamide and 2′-deoxy modifications
  作者：Kyeong Lee、Gnana Ravi、Xiao-duo Ji、Victor E Marquez、Kenneth A Jacobson

  DOI：10.1016/s0960-894x(01)00213-x

  日期：2001.5

  Novel methanocarba adenosine analogues, having the pseudo-ribose northern (N) conformation preferred at adenosine receptors (ARs), were synthesized and tested in binding assays. The 5'-uronamide modification preserved [N-6-(3-iodobenzyl)] or enhanced (N-6-methyl) affinity at A(3)ARs, while the 2'-deoxy modification reduced affinity and efficacy in a functional assay. Published by Elsevier Science Ltd.
• Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists
  作者：R. Gnana Ravi、Hak Sung Kim、Jörg Servos、Herbert Zimmermann、Kyeong Lee、Savitri Maddileti、José L. Boyer、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm010538v

  日期：2002.5.1

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.