(1'R,2'R,3'S,4'R,5'S)-4-(chloropurin-9-yl)-1-[(phenylmethoxy)methyl]-bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) | 328396-54-9

• 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-(chloropurin-9-yl)-1-[(phenylmethoxy)methyl]-bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
• CAS: 328396-54-9
• 化学式: C₂₂H₂₃ClN₄O₃
• 分子量: 426.903
• InChiKey: ZLFHLGCRAAZOKL-QTXLZRIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.78
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  71.29
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1'R,2'R,3'S,4'R,5'S)-4-(chloropurin-9-yl)-1-[(phenylmethoxy)methyl]-bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) 在 钯 四氮唑 、 甲酸 、 Dowex 50X₈-200 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.33h， 生成 [(1R,2R,3S,4R,5S)-2,3-dihydroxy-4-[6-(methylamino)purin-9-yl]-1-bicyclo[3.1.0]hexanyl]methoxy-imidazol-1-ylphosphinic acid
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  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.

  DOI：

  10.1021/jm010538v
• 作为产物：
  描述：

  6-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， 以86.7%的产率得到(1'R,2'R,3'S,4'R,5'S)-4-(chloropurin-9-yl)-1-[(phenylmethoxy)methyl]-bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
  参考文献：
  名称：

  使用闭环复分解合成以及对 (N)-methanocarba S-(4-硝基苄基)硫代肌苷衍生物的核苷转运的影响。

  摘要：

  [反应：见正文] 提出了环约束（N）-甲烷卡巴核苷和核苷酸的新合成路线。使用格鲁布斯催化剂使二烯中间体闭环，为环戊烯酮衍生物6的制备提供了新途径，环戊烯酮衍生物6是各种碳环的通用中间体。该产品几乎与母体化合物一样有效，是 es 介导的核苷转运抑制剂，在大约 30-50 nM 的浓度下，可将培养的 CCRF-CEM 细胞中尿苷的初始摄取率抑制 50%。

  DOI：

  10.1021/ol006999c

文献信息

• 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.
• Methanocarba Modification of Uracil and Adenine Nucleotides:  High Potency of Northern Ring Conformation at P2Y₁, P2Y₂, P2Y₄, and P2Y₁₁ but Not P2Y₆ Receptors
  作者：Hak Sung Kim、R. Gnana Ravi、Victor E. Marquez、Savitri Maddileti、Anna-Karin Wihlborg、David Erlinge、Malin Malmsjö、José L. Boyer、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm010369e

  日期：2002.1.1

  The potency of nucleotide antagonists at P2Y(1) receptors was enhanced by replacing the ribose moiety with a constrained carbocyclic ring (Nandanan, et al. J. Med. Chem. 2000, 43, 829842). We have now synthesized ring-constrained methanocarba analogues (in which a fused cyclopropane moiety constrains the pseudosugar ring) of adenine and uracil nucleotides, the endogenous activators of P2Y receptors. Methanocarba-adenosine 5'-triphosphate (ATP) was fixed in either a Northern (N) or a Southern (S) conformation, as defined in the pseudorotational cycle. (N)-Methanocarba-uridine was prepared from the 1-amino-pseudosugar ring by treatment with beta-ethoxyacryloyl cyanate and cyclization to form the uracil ring. Phosphorylation was carried out at the 5'-hydroxyl group through a multistep process: Reaction with phosphoramidite followed by oxidation provided the 5'-monophosphates, which then were treated with 1,1'-carbonyldiimidazole for condensation with additional phosphate groups, The ability of the analogues to stimulate phospholipase C through activation of turkey P2Y(1) or human P2Y(1), P2Y(2), P2Y(4), P2Y(6), and P2Y(11) receptors stably expressed in astrocytoma cells was measured. At recombinant human P2Y(1) and P2Y(2) receptors, (N)-methanocarba-ATP was 138- and 41-fold, respectively, more potent than racemic (S)-methanocarba-ATP as an agonist. (N)methanocarba-ATP activated P2Y(11) receptors with a potency similar to ATP. (N)-Methanocarba-uridine 5'-triphosphate (UTP) was equipotent to UTP as an agonist at human P2Y2 receptors and also activated P2Y(4) receptors with an EC50 of 85 nM. (N)-Methanocarba-uridine 5'-diphosphate (UDP) was inactive at the hP2Y(6) receptor. The vascular effects of (N)-methanocarba-UTP and (N)-methanocarba-UDP were studied in a model of the rat mesenteric artery, The triphosphate was more potent than UTP in inducing a dilatory P2Y(4) response (pEC(50) = 6.1 +/- 0.2), while the diphosphate was inactive as either an agonist or antagonist in a P2Y(6) receptor-mediated contractile response. Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors.