2'-C-methyladenosine-2',3'-acetonide | 16434-54-1

• 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: 2'-C-methyladenosine-2',3'-acetonide
• 英文别名: 2′,3′-O-isoproylidene-β-2′-methyladenosine；2'-C-methyl-2',3'-O-isopropylidene-adenosine；O^2'_,O3'-isopropylidene-2'-methyl-adenosine；[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-6-yl]methanol
• CAS: 16434-54-1
• 化学式: C₁₄H₁₉N₅O₄
• 分子量: 321.336
• InChiKey: CHEDOQJFIXMVSZ-AMJCQUEASA-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：

  2'-C-methyladenosine-2',3'-acetonide 在 氢氧化钾 、 potassium permanganate 作用下， 反应 8.0h， 以79%的产率得到(3aR,4S,6R,6aR)-6-(6-Amino-purin-9-yl)-2,2,6a-trimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid
  参考文献：
  名称：

  2‘-C-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies

  摘要：

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

  DOI：

  10.1021/jm9707737
• 作为产物：
  描述：

  6-氯-9-(2,3,5-三苯甲酰氧基-2-C-甲基-beta-D-呋喃核糖基)-9H-嘌呤 在 氨 、 对甲苯磺酸 、 2,2-二甲氧基丙烷 作用下， 反应 23.0h， 生成 2'-C-methyladenosine-2',3'-acetonide
  参考文献：
  名称：

  2‘-C-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies

  摘要：

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

  DOI：

  10.1021/jm9707737

文献信息

• Targeting <i>Mycobacterium tuberculosis</i> Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors
  作者：Matthew R. Bockman、Alvin S. Kalinda、Riccardo Petrelli、Teresa De la Mora-Rey、Divya Tiwari、Feng Liu、Surendra Dawadi、Madhumitha Nandakumar、Kyu Y. Rhee、Dirk Schnappinger、Barry C. Finzel、Courtney C. Aldrich

  DOI：10.1021/acs.jmedchem.5b00719

  日期：2015.9.24

  Mycobacterium tuberculosis (Mtb), responsible for second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an both latent and symptomatic tuberculosis (TB), remains the essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with K(D)s <= 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 mu M. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-alpha analogue over the corresponding C-2'-beta analogue, consistent with their differential whole-cell activity.
• 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.
• Liver-Targeted Prodrugs of 2‘-<i>C</i>-Methyladenosine for Therapy of Hepatitis C Virus Infection
  作者：Scott J. Hecker、K. Raja Reddy、Paul D. van Poelje、Zhili Sun、Wenjian Huang、Vaibhav Varkhedkar、M. Venkat Reddy、James M. Fujitaki、David B. Olsen、Kenneth A. Koeplinger、Serge H. Boyer、David L. Linemeyer、Malcolm MacCoss、Mark D. Erion

  DOI：10.1021/jm0701021

  日期：2007.8.1

  2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.
• 2‘-<i>C</i>-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies
  作者：Palmarisa Franchetti、Loredana Cappellacci、Stefano Marchetti、Letizia Trincavelli、Claudia Martini、Maria R. Mazzoni、Antonio Lucacchini、Mario Grifantini

  DOI：10.1021/jm9707737

  日期：1998.5.1

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.