uridine-5'-β,γ-dichloromethylenetriphosphate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: uridine-5'-β,γ-dichloromethylenetriphosphate
• 英文别名: 5'-uridylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl)anhydride；β,γ-dichloromethylene-UTP；dichloro(((((2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryloxy)(hydroxy)phosphoryl)methylphosphonic acid；[dichloro-[[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]phosphonic acid
• 化学式: C₁₀H₁₅Cl₂N₂O₁₄P₃
• 分子量: 551.061
• InChiKey: KPTMPYLAZMDWPG-XVFCMESISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  250
• 氢给体数：
  7
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  uridine-5'-β,γ-dichloromethylenetriphosphate 、 尿苷5-单磷酸 在 三正丁胺 、 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 49.0h， 生成 P1,P4-di(uridine 5''-)beta,gamma-dichloromethlyenetetraphosphate
  参考文献：
  名称：

  Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

  摘要：

  The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modi. cation, found previously to enhance P2Y2 receptor potency, could be combined with other favorable modi. cations to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha, beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1] glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P-1-(uridine-5')-P-4-(2'-deoxycytidine-5') tetraphosphate), a potent and selective P2Y(2) receptor agonist. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2008.05.013
• 作为产物：
  描述：

  在 水 、 三乙基碳酸氢铵缓冲液 作用下， 反应 1.0h， 生成 uridine-5'-β,γ-dichloromethylenetriphosphate
  参考文献：
  名称：

  Structural Modifications of UMP, UDP, and UTP Leading to Subtype-Selective Agonists for P2Y₂, P2Y₄, and P2Y₆ Receptors

  摘要：

  A large series of derivatives and analogues of the uracil nucleotides UMP, UDP, and UTP with modifications in various positions of the uracil moiety and/or the phosphate groups were synthesized and evaluated at human P2Y(2), P2Y(4), and P2Y(6) receptors. 2-(Ar)alkylthio substitution of UMP and UDP was best tolerated by the P2Y(2) receptor, 2-Phenethylthio-UMP (13e) showed an EC50 value of 1.3 mu M at P2Y(2) and > 70-fold selectivity versus P2Y(4) and P2Y(6) receptors. Substitution of the 2-keto group in UMP by NH (13g, iso-CMP) resulted in the first potent and selective P2Y(4) agonist (EC50 4.98 mu M > 20-fold selective vs P2Y(2) and P2Y(6)). In contrast, :replacement of the 2-keto function in UDP by NH yielded a potent P2Y(2) agonist (12g, iso-CDP, EC50 = 0.604 mu M, > 100-fold selective). In an attempt to obtain metabolically stable UTP analogues, beta,gamma-dichloro- and beta,gamma-difluoro-methylene-UTP derivatives were synthesized. The triphosphate modifications were much better tolerated by P2Y(2), and in some cases also by P2Y(6), than by P2Y(4) receptors. 4-Thio-beta,gamma-difluoromethylene-UTP (14g) was a potent P2Y(2) agonist with an EC50 value of 0.134 mu M and > 50-fold selectivity. N3-Phenacyl-beta,gamma-dichloromethylene-UTP (14b) proved to be a potent P2Y(6) receptor agonist (EC50 0.142 mu M) with high selectivity versus P2Y(4) (50-fold) and moderate selectivity versus P2Y(2) receptors (6-fold).

  DOI：

  10.1021/jm1016297

文献信息

• 4,5-Dicyanoimidazole-promoted synthesis of dinucleoside polyphosphates and their analogs
  作者：Qi Sun、Shan-Shan Gong、Si Liu、Jian Sun、Guo-Dong Liu、Cha Ma

  DOI：10.1016/j.tet.2014.05.013

  日期：2014.7
• Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists
  作者：Hyojin Ko、Rhonda L. Carter、Liesbet Cosyn、Riccardo Petrelli、Sonia de Castro、Pedro Besada、Yixing Zhou、Loredana Cappellacci、Palmarisa Franchetti、Mario Grifantini、Serge Van Calenbergh、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1016/j.bmc.2008.05.013

  日期：2008.6

  The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modi. cation, found previously to enhance P2Y2 receptor potency, could be combined with other favorable modi. cations to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha, beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1] glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P-1-(uridine-5')-P-4-(2'-deoxycytidine-5') tetraphosphate), a potent and selective P2Y(2) receptor agonist. Published by Elsevier Ltd.
• Structural Modifications of UMP, UDP, and UTP Leading to Subtype-Selective Agonists for P2Y₂, P2Y₄, and P2Y₆ Receptors
  作者：Ali El-Tayeb、Aidong Qi、Robert A. Nicholas、Christa E. Müller

  DOI：10.1021/jm1016297

  日期：2011.4.28

  A large series of derivatives and analogues of the uracil nucleotides UMP, UDP, and UTP with modifications in various positions of the uracil moiety and/or the phosphate groups were synthesized and evaluated at human P2Y(2), P2Y(4), and P2Y(6) receptors. 2-(Ar)alkylthio substitution of UMP and UDP was best tolerated by the P2Y(2) receptor, 2-Phenethylthio-UMP (13e) showed an EC50 value of 1.3 mu M at P2Y(2) and > 70-fold selectivity versus P2Y(4) and P2Y(6) receptors. Substitution of the 2-keto group in UMP by NH (13g, iso-CMP) resulted in the first potent and selective P2Y(4) agonist (EC50 4.98 mu M > 20-fold selective vs P2Y(2) and P2Y(6)). In contrast, :replacement of the 2-keto function in UDP by NH yielded a potent P2Y(2) agonist (12g, iso-CDP, EC50 = 0.604 mu M, > 100-fold selective). In an attempt to obtain metabolically stable UTP analogues, beta,gamma-dichloro- and beta,gamma-difluoro-methylene-UTP derivatives were synthesized. The triphosphate modifications were much better tolerated by P2Y(2), and in some cases also by P2Y(6), than by P2Y(4) receptors. 4-Thio-beta,gamma-difluoromethylene-UTP (14g) was a potent P2Y(2) agonist with an EC50 value of 0.134 mu M and > 50-fold selectivity. N3-Phenacyl-beta,gamma-dichloromethylene-UTP (14b) proved to be a potent P2Y(6) receptor agonist (EC50 0.142 mu M) with high selectivity versus P2Y(4) (50-fold) and moderate selectivity versus P2Y(2) receptors (6-fold).