4-氨基-3-(1-萘基甲基)-1H-吡唑并[3,4-d]嘧啶-1-(beta-D-呋喃核糖基-5’-三磷酸酯) | 476371-81-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 4-氨基-3-(1-萘基甲基)-1H-吡唑并[3,4-d]嘧啶-1-(beta-D-呋喃核糖基-5’-三磷酸酯)
• 英文名称: (2S,3R,4S,5R)-2-(4-amino-3-naphthalen-1-ylmethylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol-5'-triphosphate
• 英文别名: 1-[5-O-(Hydroxy{[hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl)-beta-D-ribofuranosyl]-3-[(naphthalen-1-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine；[[(2R,3S,4R,5R)-5-[4-amino-3-(naphthalen-1-ylmethyl)pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate
• CAS: 476371-81-0
• 化学式: C₂₁H₂₄N₅O₁₃P₃
• 分子量: 647.369
• InChiKey: NPKUTVNELHUNPS-QTQZEZTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.4
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  279
• 氢给体数：
  7
• 氢受体数：
  17

反应信息

• 作为产物：
  描述：

  萘-1-基乙酰氯 在 盐酸肼 、 氨 、 四氯化锡 、 sodium hydride 、 碳酸氢钠 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 乙腈 为溶剂， 生成 4-氨基-3-(1-萘基甲基)-1H-吡唑并[3,4-d]嘧啶-1-(beta-D-呋喃核糖基-5’-三磷酸酯)
  参考文献：
  名称：

  Inhibitor Scaffolds as New Allele Specific Kinase Substrates

  摘要：

  The elucidation of protein kinase signaling networks is challenging due to the large size of the protein kinase superfamily (> 500 human kinases). Here we describe a new class of orthogonal triphosphate substrate analogues for the direct labeling of analogue-specific kinase protein targets. These analogues were constructed as derivatives of the Src family kinase inhibitor PP1 and were designed based on the crystal structures of PP1 bound to HCK and N-6-(benzyl)-ADP bound to c-Src (T338G). 3-Benzylpyrazolopyrimidine triphosphate (3-benzyl-PPTP) proved to be a substrate for a mutant of the MAP kinase p38 (p38-T106G/A157L/L167A). 3-Benzyl-PPTP was preferred by v-Src (T338G) (k(cat)/K-M = 3.2 x 10(6) min(-1) M-1) over ATP or the previously described ATP analogue, N-6 (benzyl) ATP. For the kinase CDK2 (F80G)/cyclin E, 3-benzyl-PPTP demonstrated catalytic efficiency (k(cat)/K-M = 2.6 x 10(4) min(-1) M-1) comparable to ATP (k(cat)/K-M = 5.0 x 10(4) min(-1) M-1) largely due to a significantly better K-M (6.4 muM vs 530 muM). In kinase protein substrate labeling experiments both 3-benzyl-PPTP and 3-phenyl-PPTP prove to be over 4 times more orthogonal than N-6-(benzyl)-ATP with respect to the wild-type kinases found in murine spleenocyte cell lysates. These experiments also demonstrate that [gamma-P-32]-3-benzyl-PPTP is an excellent phosphodonor for labeling the direct protein substrates of CDK2 (F80G)/E in murine spleenocyte cell lysates, even while competing with cellular levels (4 mM) of unlabeled ATP. The fact that this new more highly orthogonal nucleotide is accepted by three widely divergent kinases studied here suggests that it is likely to be generalizable across the entire kinase superfamily.

  DOI：

  10.1021/ja0264798

文献信息

• Inhibitor Scaffolds as New Allele Specific Kinase Substrates
  作者：Brian C. Kraybill、Lisa L. Elkin、Justin D. Blethrow、David O. Morgan、Kevan M. Shokat

  DOI：10.1021/ja0264798

  日期：2002.10.1

  The elucidation of protein kinase signaling networks is challenging due to the large size of the protein kinase superfamily (> 500 human kinases). Here we describe a new class of orthogonal triphosphate substrate analogues for the direct labeling of analogue-specific kinase protein targets. These analogues were constructed as derivatives of the Src family kinase inhibitor PP1 and were designed based on the crystal structures of PP1 bound to HCK and N-6-(benzyl)-ADP bound to c-Src (T338G). 3-Benzylpyrazolopyrimidine triphosphate (3-benzyl-PPTP) proved to be a substrate for a mutant of the MAP kinase p38 (p38-T106G/A157L/L167A). 3-Benzyl-PPTP was preferred by v-Src (T338G) (k(cat)/K-M = 3.2 x 10(6) min(-1) M-1) over ATP or the previously described ATP analogue, N-6 (benzyl) ATP. For the kinase CDK2 (F80G)/cyclin E, 3-benzyl-PPTP demonstrated catalytic efficiency (k(cat)/K-M = 2.6 x 10(4) min(-1) M-1) comparable to ATP (k(cat)/K-M = 5.0 x 10(4) min(-1) M-1) largely due to a significantly better K-M (6.4 muM vs 530 muM). In kinase protein substrate labeling experiments both 3-benzyl-PPTP and 3-phenyl-PPTP prove to be over 4 times more orthogonal than N-6-(benzyl)-ATP with respect to the wild-type kinases found in murine spleenocyte cell lysates. These experiments also demonstrate that [gamma-P-32]-3-benzyl-PPTP is an excellent phosphodonor for labeling the direct protein substrates of CDK2 (F80G)/E in murine spleenocyte cell lysates, even while competing with cellular levels (4 mM) of unlabeled ATP. The fact that this new more highly orthogonal nucleotide is accepted by three widely divergent kinases studied here suggests that it is likely to be generalizable across the entire kinase superfamily.