N4-methoxycytidine 5-α,β-methylenediphosphate triethylammonium salt

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N4-methoxycytidine 5-α,β-methylenediphosphate triethylammonium salt
• 英文别名: N,N-diethylethanamine;[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(methoxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid
• 化学式: C₆H₁₅N*C₁₁H₁₉N₃O₁₁P₂
• 分子量: 532.425
• InChiKey: FDAHZSCVHWONGQ-RQDZQORCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.48
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  211
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  胞苷 在 吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 N4-methoxycytidine 5-α,β-methylenediphosphate triethylammonium salt
  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

文献信息

• Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y₆ Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modifications
  作者：Hiroshi Maruoka、Matthew O. Barrett、Hyojin Ko、Dilip K. Tosh、Artem Melman、Lauren E. Burianek、Ramachandran Balasubramanian、Barkin Berk、Stefano Costanzi、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm100287t

  日期：2010.6.10

  The P2Y(6) receptor is a cytoprotective G-protein-coupled receptor (GPCR) activated by UDP (EC50 = 0.30 mu M). We compared and combined modifications to enhance P2Y(6) receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as alpha,beta-methylene and extension of the terminal phosphate group into gamma-esters of UTP analogues. The conformationally constrained (S)-methanocarba-UDP is a full agonist (EC50 = 0.042 mu M). 4-Methoxyimino modification of pyrimidine enhanced P2Y(6), preserved P2Y(2) and P2Y(4), and abolished P2Y(14) receptor potency, in the appropriate nucleotide. N-4-Benzyloxy-CDP (15, MRS2964) and N-4-methoxy-Cp3U Cp3U (12, MRS2957) were potent, selective P2Y(6) receptor agonists (EC50 of 0.026 and 0.012 mu M, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-gamma-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y(6) receptor potency but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N-4-methoxycytidine 5'-triphospho-gamma-[1]glucose were active (EC50 of 2.47 and 0.18 mu M, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y(6) receptor agonists may be enhanced by modest structural changes.
• 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。