1-((2S,3R,4S,5R)-3,4-dibenzoyl-5-benzoylmethyltetrahydrofuran-2-yl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | 476371-71-8

• 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: 1-((2S,3R,4S,5R)-3,4-dibenzoyl-5-benzoylmethyltetrahydrofuran-2-yl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine
• 英文别名: [(2R,3R,4R,5R)-5-(4-amino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dibenzoyloxyoxolan-2-yl]methyl benzoate
• CAS: 476371-71-8
• 化学式: C₃₇H₂₉N₅O₇
• 分子量: 655.667
• InChiKey: BFYBMKNQCRZYNM-CIBJAQMISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  49
• 可旋转键数：
  12
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  158
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  1,1-二氰基-2-甲氧基-2-(苯基)乙烯 在 盐酸肼 、 四氯化锡 、 三乙胺 作用下， 以 乙醇 、 乙腈 为溶剂， 生成 1-((2S,3R,4S,5R)-3,4-dibenzoyl-5-benzoylmethyltetrahydrofuran-2-yl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine
  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

• ATG7 inhibitors and the uses thereof
  申请人：Millennium Pharmaceuticals, Inc.

  公开号：US10865208B2

  公开（公告）日：2020-12-15

  Disclosed are chemical entities which are compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2, and Ra have the values described herein. Chemical entities according to the disclosure can be useful as inhibitors of ATG7. Further provided are pharmaceutical compositions comprising a chemical entity of the disclosure and methods of using the compositions in the treatment of cancer.

  所公开的化学实体为式（I）化合物：或其药学上可接受的盐，其中 R1、R2 和 Ra 具有本文所述的值。根据本公开的化学实体可用作 ATG7 的抑制剂。进一步提供了包含本公开的化学实体的药物组合物，以及使用该组合物治疗癌症的方法。