N⁶-[(1S)-methyl-2-phenylethyl]-9H-(6-O-benzyl-3,4-O-benzylidene-1-deoxy-β-D-psicofuranosyl)adenine | 406479-36-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: N⁶-[(1S)-methyl-2-phenylethyl]-9H-(6-O-benzyl-3,4-O-benzylidene-1-deoxy-β-D-psicofuranosyl)adenine
• 英文别名: 9-[(3aR,4R,6R,6aR)-4-methyl-2-phenyl-6-(phenylmethoxymethyl)-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]-N-[(2S)-1-phenylpropan-2-yl]purin-6-amine
• CAS: 406479-36-5
• 化学式: C₃₄H₃₅N₅O₄
• 分子量: 577.683
• InChiKey: BEOUZFJLHJNTKN-XEGRYWJBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  92.6
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N⁶-[(1S)-methyl-2-phenylethyl]-9H-(6-O-benzyl-3,4-O-benzylidene-1-deoxy-β-D-psicofuranosyl)adenine 在 10percent Pd/C ammonium formate 作用下， 以 甲醇 为溶剂， 反应 3.5h， 以50%的产率得到N⁶-[(1S)-1-methyl-2-phenylethyl]-9H-(1-deoxy-β-D-psicofuranosyl)adenine
  参考文献：
  名称：

  Ribose-Modified Nucleosides as Ligands for Adenosine Receptors:  Synthesis, Conformational Analysis, and Biological Evaluation of 1‘-C-Methyl Adenosine Analogues

  摘要：

  1'-C-Methyl analogues of adenosine and selective adenosine A, receptor agonists, such as N-[(1R)-1-methyl-2-phenylethyl]adenosine ((R)-PIA) and N-6-cyclopentyladenosine, were synthesized to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in rat brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 1'-C-methyl modification in adenosine resulted in a decrease of affinity, particularly at A(1) and A(2A) receptors. When this modification was combined with N-6 substitutions with groups that induce high potency and selectivity at A(3) receptors, the high affinity was in part restored and the selectivity was increased. The most potent compound proved to be the V-C-methyl analogue of (R)-PIA with a K-i of 23 nM for the displacement of [H-3]CHA binding from rat brain A(1) receptors and a >435-fold selectivity over A(2A) receptors. In functional assays, these compounds inhibited forskolin-stimulated adenylate cyclase with IC50 values ranging from 0.065 to 3.4 muM, acting as full agonists. Conformational analysis based on vicinal proton-proton J-coupling constants and molecular mechanics calculations using the MM2 force field proved that the methyl group on C1' in adenosine has a pronounced impact on the furanose conformation by driving its conformational equilibrium toward the north, gamma+, syn form.

  DOI：

  10.1021/jm0102755
• 作为产物：
  描述：

  2-O-acetyl-6-O-benzyl-3,4-O-benzylidene-1-deoxy-D-psicofuranose 在 二氯乙基铝 作用下， 以 乙醇 、 甲苯 、 乙腈 为溶剂， 反应 17.0h， 生成 N⁶-[(1S)-methyl-2-phenylethyl]-9H-(6-O-benzyl-3,4-O-benzylidene-1-deoxy-β-D-psicofuranosyl)adenine
  参考文献：
  名称：

  Ribose-Modified Nucleosides as Ligands for Adenosine Receptors:  Synthesis, Conformational Analysis, and Biological Evaluation of 1‘-C-Methyl Adenosine Analogues

  摘要：

  1'-C-Methyl analogues of adenosine and selective adenosine A, receptor agonists, such as N-[(1R)-1-methyl-2-phenylethyl]adenosine ((R)-PIA) and N-6-cyclopentyladenosine, were synthesized to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in rat brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 1'-C-methyl modification in adenosine resulted in a decrease of affinity, particularly at A(1) and A(2A) receptors. When this modification was combined with N-6 substitutions with groups that induce high potency and selectivity at A(3) receptors, the high affinity was in part restored and the selectivity was increased. The most potent compound proved to be the V-C-methyl analogue of (R)-PIA with a K-i of 23 nM for the displacement of [H-3]CHA binding from rat brain A(1) receptors and a >435-fold selectivity over A(2A) receptors. In functional assays, these compounds inhibited forskolin-stimulated adenylate cyclase with IC50 values ranging from 0.065 to 3.4 muM, acting as full agonists. Conformational analysis based on vicinal proton-proton J-coupling constants and molecular mechanics calculations using the MM2 force field proved that the methyl group on C1' in adenosine has a pronounced impact on the furanose conformation by driving its conformational equilibrium toward the north, gamma+, syn form.

  DOI：

  10.1021/jm0102755

文献信息

• Ribose-Modified Nucleosides as Ligands for Adenosine Receptors:  Synthesis, Conformational Analysis, and Biological Evaluation of 1‘-<i>C</i>-Methyl Adenosine Analogues
  作者：Loredana Cappellacci、Grazia Barboni、Micaela Palmieri、Michela Pasqualini、Mario Grifantini、Barbara Costa、Claudia Martini、Palmarisa Franchetti

  DOI：10.1021/jm0102755

  日期：2002.3.1

  1'-C-Methyl analogues of adenosine and selective adenosine A, receptor agonists, such as N-[(1R)-1-methyl-2-phenylethyl]adenosine ((R)-PIA) and N-6-cyclopentyladenosine, were synthesized to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in rat brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 1'-C-methyl modification in adenosine resulted in a decrease of affinity, particularly at A(1) and A(2A) receptors. When this modification was combined with N-6 substitutions with groups that induce high potency and selectivity at A(3) receptors, the high affinity was in part restored and the selectivity was increased. The most potent compound proved to be the V-C-methyl analogue of (R)-PIA with a K-i of 23 nM for the displacement of [H-3]CHA binding from rat brain A(1) receptors and a >435-fold selectivity over A(2A) receptors. In functional assays, these compounds inhibited forskolin-stimulated adenylate cyclase with IC50 values ranging from 0.065 to 3.4 muM, acting as full agonists. Conformational analysis based on vicinal proton-proton J-coupling constants and molecular mechanics calculations using the MM2 force field proved that the methyl group on C1' in adenosine has a pronounced impact on the furanose conformation by driving its conformational equilibrium toward the north, gamma+, syn form.