9H-(3-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)adenine | 16831-90-6

• 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: 9H-(3-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)adenine
• 英文别名: [(3aR,4R,6R,6aR)-6-(6-aminopurin-9-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methanol
• CAS: 16831-90-6
• 化学式: C₁₄H₁₉N₅O₄
• 分子量: 321.336
• InChiKey: ZFSZJQZDNMVXFJ-MEUNMDNISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  9H-(3-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)adenine 在 2,2,6,6-四甲基哌啶氧化物 、 碘苯二乙酸 、 水 作用下， 以 乙腈 为溶剂， 反应 3.0h， 以54%的产率得到1-deoxy-1-(6-amino-9H-purin-9-yl)-3-C-methyl-2,3-O-isopropylidene-β-D-ribofuranoic acid
  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：

  2,2-二甲氧基丙烷 、 3'-C-Methyladenosine 在 camphor-10-sulfonic acid 作用下， 以 丙酮 为溶剂， 反应 11.0h， 以58%的产率得到9H-(3-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)adenine
  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

• Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues
  作者：Riccardo Petrelli、Yuk Yin Sham、Liqiang Chen、Krzysztof Felczak、Eric Bennett、Daniel Wilson、Courtney Aldrich、Jose S. Yu、Loredana Cappellacci、Palmarisa Franchetti、Mario Grifantini、Francesca Mazzola、Michele Di Stefano、Giulio Magni、Krzysztof W. Pankiewicz

  DOI：10.1016/j.bmc.2009.06.013

  日期：2009.8

  Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC50 = 110 mu M and IC50 = 87 mu M, respectively) and Mycobacterium tuberculosis NAD kinase (IC50 = 80 mu M and IC50 = 45 mu M, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC50 = 6 mu M) and mycobacterium NAD kinase (IC50 = 14-19 mu M reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation. (C) 2009 Elsevier Ltd. All rights reserved.
• 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.