(1'S,2'R,3'S,4'R,5'S)-4-(2,4(H,3H)-dioxopyrimidin-1-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)

• 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'S,2'R,3'S,4'R,5'S)-4-(2,4(H,3H)-dioxopyrimidin-1-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
• 英文别名: 1-[(1R,2R,4S,5R,6S)-2-(hydroxymethyl)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]pyrimidine-2,4-dione
• 化学式: C₁₄H₁₈N₂O₅
• 分子量: 294.307
• InChiKey: GFOOHBZCDGXCLP-ZDGLEYBBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  88.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4-(2,4(H,3H)-dioxopyrimidin-1-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) 在 2,3-dimethyl-1-(phenylsulfonyl)-1H-imidazolium triflate 、 N,N-二乙基亚磷酰胺二叔丁酯 、 2H-tetrazole 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.75h， 生成 MRS4387
  参考文献：
  名称：

  含有（S）-甲氨基甲环作为P2Y 6受体激动剂的嘧啶核苷酸

  摘要：

  UDP激活的P2Y 6受体（P2Y 6 R）的激动剂和拮抗剂已被建议用于治疗，例如癌症，炎症，神经退行性疾病和糖尿病。合成了含有南双环[3.1.0]己烷（（S）-甲氨基甲酸）环系统代替核糖环的尿嘧啶核苷酸，并在钙动员测定中显示为有效的P2Y 6 R激动剂。（S）-甲氨基甲酸酯修饰与嘧啶上的5-碘或4-甲氧基亚氨基相容，但与α，β-亚甲基5'-二磷酸不相容。（S）-Methanocarba二核苷酸效力与假定在P2Y 6结合的近端核苷上的N 4-甲氧基修饰兼容R与UDP类似；在远端核苷部分上优选（N）-甲氨基甲酸酯。这表明远端二核苷酸P2Y 6 R结合位点更喜欢可以达到（N）构象的核糖样基团，而不是（S）。通过同源性建模，对接和分子动力学模拟对二核苷酸结合进行建模，这表明凭经验发现了相同的核糖构象偏好。

  DOI：

  10.1039/c7md00397h
• 作为产物：
  描述：

  (1R,2R,4S,5R,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-amine 在 钯 甲酸 、 硫酸 、 对甲苯磺酸 作用下， 以 甲醇 、 苯 为溶剂， 反应 10.34h， 生成 (1'S,2'R,3'S,4'R,5'S)-4-(2,4(H,3H)-dioxopyrimidin-1-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
  参考文献：
  名称：

  Methanocarba Modification of Uracil and Adenine Nucleotides:  High Potency of Northern Ring Conformation at P2Y₁, P2Y₂, P2Y₄, and P2Y₁₁ but Not P2Y₆ Receptors

  摘要：

  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.

  DOI：

  10.1021/jm010369e

文献信息

• Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y₆ receptor agonists
  作者：Kiran S. Toti、Shanu Jain、Antonella Ciancetta、Ramachandran Balasubramanian、Saibal Chakraborty、Ryan Surujdin、Zhen-Dan Shi、Kenneth A. Jacobson

  DOI：10.1039/c7md00397h

  日期：——

  modification on the proximal nucleoside that is assumed to bind at the P2Y6R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y6R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested

  UDP激活的P2Y 6受体（P2Y 6 R）的激动剂和拮抗剂已被建议用于治疗，例如癌症，炎症，神经退行性疾病和糖尿病。合成了含有南双环[3.1.0]己烷（（S）-甲氨基甲酸）环系统代替核糖环的尿嘧啶核苷酸，并在钙动员测定中显示为有效的P2Y 6 R激动剂。（S）-甲氨基甲酸酯修饰与嘧啶上的5-碘或4-甲氧基亚氨基相容，但与α，β-亚甲基5'-二磷酸不相容。（S）-Methanocarba二核苷酸效力与假定在P2Y 6结合的近端核苷上的N 4-甲氧基修饰兼容R与UDP类似；在远端核苷部分上优选（N）-甲氨基甲酸酯。这表明远端二核苷酸P2Y 6 R结合位点更喜欢可以达到（N）构象的核糖样基团，而不是（S）。通过同源性建模，对接和分子动力学模拟对二核苷酸结合进行建模，这表明凭经验发现了相同的核糖构象偏好。
• 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.