(2S,3R,4R,5R)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-N,4-dimethyloxolane-2-carboxamide | 849241-98-1

• 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: (2S,3R,4R,5R)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-N,4-dimethyloxolane-2-carboxamide
• CAS: 849241-98-1
• 化学式: C₁₉H₂₀ClIN₆O₄
• 分子量: 558.763
• InChiKey: WQOZWPKZSRLJFH-CKFGLLJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  134
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,3R,4R,5R)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-N,4-dimethyloxolane-2-carboxamide 、 甲胺 以 四氢呋喃 为溶剂， 反应 20.0h， 以45%的产率得到(2S,3R,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]-2-(methylamino)purin-9-yl]-N,4-dimethyloxolane-2-carboxamide
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists

  摘要：

  A number of 3'-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2'-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A(1), A(2A), and A(3) receptors in bovine brain membranes showed that the X-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N-6-substitution with groups that induce high potency and selectivity at A(1) receptor, the affinity and selectivity were increased. However, all X-C-methyl derivatives proved to be very less active than the corresponding 2'-C-methyl analogues. The most active compound was found to be 3'-Me-CPA which displayed a K-i value of 0.35 muM at A(1) receptor and a selectivity for A(1) vs A(2A) and A(3) receptors higher than 28-fold. 2'-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A(1) receptor with a K-i value of 3.3 nM and 2903- and 341-fold selective vs human A(2A) and A(3) receptors, respectively. In functional assay, 3'-Me-CPA, 3'-Me-CCPA, and 2-Cl-3'-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC50 values ranging from 0.3 to 4.9 muM, acting as full agonists. A rhodopsin-based model of the bovine A(1)AR was built to rationalize the higher affinity and selectivity of 2'-C-methyl derivatives of N-6-substituted-adenosine compared to that of 3'-C-methyl analogues. In the docking exploration, it was found that 2'-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA(1)AR which were not preserved in the molecular dynamics simulation of 3'-Me-CCPA/bA(1)AR complex.

  DOI：

  10.1021/jm049408n
• 作为产物：
  描述：

  2,6-dichloro-9-(2-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-9H-purine 在 甲酸 、 氯化亚砜 、 2,2,6,6-四甲基哌啶氧化物 、 碘苯二乙酸 、 TEA 、 camphor-10-sulfonic acid 、 氨 、 水 作用下， 以 甲醇 、 乙醇 、 丙酮 、 乙腈 为溶剂， 反应 25.0h， 生成 (2S,3R,4R,5R)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-N,4-dimethyloxolane-2-carboxamide
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists

  摘要：

  A number of 3'-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2'-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A(1), A(2A), and A(3) receptors in bovine brain membranes showed that the X-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N-6-substitution with groups that induce high potency and selectivity at A(1) receptor, the affinity and selectivity were increased. However, all X-C-methyl derivatives proved to be very less active than the corresponding 2'-C-methyl analogues. The most active compound was found to be 3'-Me-CPA which displayed a K-i value of 0.35 muM at A(1) receptor and a selectivity for A(1) vs A(2A) and A(3) receptors higher than 28-fold. 2'-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A(1) receptor with a K-i value of 3.3 nM and 2903- and 341-fold selective vs human A(2A) and A(3) receptors, respectively. In functional assay, 3'-Me-CPA, 3'-Me-CCPA, and 2-Cl-3'-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC50 values ranging from 0.3 to 4.9 muM, acting as full agonists. A rhodopsin-based model of the bovine A(1)AR was built to rationalize the higher affinity and selectivity of 2'-C-methyl derivatives of N-6-substituted-adenosine compared to that of 3'-C-methyl analogues. In the docking exploration, it was found that 2'-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA(1)AR which were not preserved in the molecular dynamics simulation of 3'-Me-CCPA/bA(1)AR complex.

  DOI：

  10.1021/jm049408n

文献信息

• Synthesis, Biological Evaluation, and Molecular Modeling of Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists
  作者：Loredana Cappellacci、Palmarisa Franchetti、Michela Pasqualini、Riccardo Petrelli、Patrizia Vita、Antonio Lavecchia、Ettore Novellino、Barbara Costa、Claudia Martini、Karl-Norbert Klotz、Mario Grifantini

  DOI：10.1021/jm049408n

  日期：2005.3.1

  A number of 3'-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2'-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A(1), A(2A), and A(3) receptors in bovine brain membranes showed that the X-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N-6-substitution with groups that induce high potency and selectivity at A(1) receptor, the affinity and selectivity were increased. However, all X-C-methyl derivatives proved to be very less active than the corresponding 2'-C-methyl analogues. The most active compound was found to be 3'-Me-CPA which displayed a K-i value of 0.35 muM at A(1) receptor and a selectivity for A(1) vs A(2A) and A(3) receptors higher than 28-fold. 2'-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A(1) receptor with a K-i value of 3.3 nM and 2903- and 341-fold selective vs human A(2A) and A(3) receptors, respectively. In functional assay, 3'-Me-CPA, 3'-Me-CCPA, and 2-Cl-3'-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC50 values ranging from 0.3 to 4.9 muM, acting as full agonists. A rhodopsin-based model of the bovine A(1)AR was built to rationalize the higher affinity and selectivity of 2'-C-methyl derivatives of N-6-substituted-adenosine compared to that of 3'-C-methyl analogues. In the docking exploration, it was found that 2'-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA(1)AR which were not preserved in the molecular dynamics simulation of 3'-Me-CCPA/bA(1)AR complex.