(2S,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol | 476371-75-2

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 吡唑并[3，4-d]嘧啶糖苷
• 英文名称: (2S,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol
• 英文别名: 3-phenyl-4-amino-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine；(2R,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 476371-75-2
• 化学式: C₁₆H₁₇N₅O₄
• 分子量: 343.342
• InChiKey: JGXKIHSISJOKFQ-RVXWVPLUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  140
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol 在 三氯氧磷 、 三正丁胺 、 焦磷酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以3%的产率得到(2S,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol-5'-triphosphate
  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
• 作为产物：
  描述：

  1-((2S,3R,4S,5R)-3,4-dibenzoyl-5-benzoylmethyltetrahydrofuran-2-yl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine 在 氨 作用下， 以 甲醇 为溶剂， 以81%的产率得到(2S,3R,4S,5R)-2-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol
  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

• Revisiting Pyrazolo[3,4-<i>d</i>]pyrimidine Nucleosides as Anti-<i>Trypanosoma cruzi</i> and Antileishmanial Agents
  作者：Jakob Bouton、Ludmila Ferreira de Almeida Fiuza、Camila Cardoso Santos、Maria Angela Mazzarella、Maria de Nazaré Correia Soeiro、Louis Maes、Izet Karalic、Guy Caljon、Serge Van Calenbergh

  DOI：10.1021/acs.jmedchem.1c00135

  日期：2021.4.8

  for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine)

  恰加斯病和内脏利什曼病是导致世界各地众多死亡的两种被忽视的热带病。对于这两种方法，目前的治疗方法都远远不够，导致对新药发现的持续需求。由于两种运动质体寄生虫均无法进行嘌呤从头合成，因此它们依赖于嘌呤挽救途径，从而使它们能够从宿主处获取和加工嘌呤来满足其需求。因此，嘌呤核苷类似物构成潜在抗寄生虫剂的逻辑来源。天然产物结核菌素（7-脱氮杂腺苷）的早期优化工作涉及对核碱基7位和呋喃核糖3'位的修饰，从而产生了具有强效抗布鲁氏锥虫和抗克鲁氏锥虫的类似物活动。在这项工作中，我们报告了3'-和7-修饰的吡唑并[3,4- d ]嘧啶核苷的设计和合成，并评估了它们作为抗克氏锥虫和抗疟药的潜力。选择了一种化合物在急性恰加斯病小鼠模型中进行体内评估。