(1R,2R,3S,4R,5S)-4-(2-iodo-6-(2-phenylethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane | 1383554-58-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (1R,2R,3S,4R,5S)-4-(2-iodo-6-(2-phenylethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane
• CAS: 1383554-58-2
• 化学式: C₂₂H₂₄IN₅O₂
• 分子量: 517.369
• InChiKey: UDPIBTMTPKTYJF-YKJOPOJSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  74.09
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1R,2R,3S,4R,5S)-4-(2-iodo-6-(2-phenylethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三氟甲磺酸 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,2R,3S,4R,5S)-4-(6-(2-phenylethylamino)-2-(phenylethynyl)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol
  参考文献：
  名称：

  Truncated Nucleosides as A₃ Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions

  摘要：

  C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane [(N)-methanocarba] ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleosides containing alkyl or alkylaryl groups at the N-6 position were low-efficacy agonists or antagonists of the human A(3)AR with high selectivity. Higher hA(3)AR affinity was associated with N-6-methyl and ethyl (K-i = 3-6 nM) than with N-6-arylallcyl groups. However, combined C2-phenylethynyl and N-6-2-phenylethyl substitutions in selective antagonist 15 provided a K-i of 20 nM. Differences between 4'-truncated and nontruncated analogues of extended C2-p-biphenylethynyl substitution suggested a ligand reorientation in AR binding, dominated by bulky N-6 groups in analogues lacking a stabilizing S'-uronamide moiety. Thus, 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N-6 groups, but reduced efficacy in A(3)AR-induced inhibition of adenylate cyclase.

  DOI：

  10.1021/ml300107e
• 作为产物：
  描述：

  (3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]-cyclopenta[1,2-d][1,3]dioxol-5-ol 在 偶氮二甲酸二异丙酯 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 (1R,2R,3S,4R,5S)-4-(2-iodo-6-(2-phenylethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Truncated Nucleosides as A₃ Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions

  摘要：

  C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane [(N)-methanocarba] ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleosides containing alkyl or alkylaryl groups at the N-6 position were low-efficacy agonists or antagonists of the human A(3)AR with high selectivity. Higher hA(3)AR affinity was associated with N-6-methyl and ethyl (K-i = 3-6 nM) than with N-6-arylallcyl groups. However, combined C2-phenylethynyl and N-6-2-phenylethyl substitutions in selective antagonist 15 provided a K-i of 20 nM. Differences between 4'-truncated and nontruncated analogues of extended C2-p-biphenylethynyl substitution suggested a ligand reorientation in AR binding, dominated by bulky N-6 groups in analogues lacking a stabilizing S'-uronamide moiety. Thus, 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N-6 groups, but reduced efficacy in A(3)AR-induced inhibition of adenylate cyclase.

  DOI：

  10.1021/ml300107e

文献信息

• Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A₃ Adenosine Receptors: Affinity Enhancement by <i>N</i>⁶-(2-Phenylethyl) Substitution
  作者：Dilip K. Tosh、Veronica Salmaso、Harsha Rao、Amelia Bitant、Courtney L. Fisher、David I. Lieberman、Helmut Vorbrüggen、Marc L. Reitman、Oksana Gavrilova、Zhan-Guo Gao、John A. Auchampach、Kenneth A. Jacobson

  DOI：10.1021/acs.jmedchem.0c00235

  日期：2020.4.23

  N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions

  与N6-（2-苯乙基）相比，多巴胺衍生的N6-取代基在截短的（N）-甲氨基甲酸（双环[3.1.0]己基）腺苷中具有较高的A3腺苷受体（AR）亲和力/选择性，例如C2-苯基乙炔类似物15（MRS7591，Ki = 10.9 / 17.8 nM，在人/小鼠A3AR处）。15是体外的部分激动剂（hA3AR，cAMP抑制，31％Emax； mA3AR，[35S]GTP-γ-S结合，16％Emax），并且在体内也拮抗hA3AR。N6-（2-苯乙基）部分的远端H键取代通过与细胞外环的极性相互作用特别增强了mA3AR亲和力，这是通过使用对接和分子动力学模拟和新构建的mA3AR和hA3AR同源性模型进行预测的。这些杂合模型基于TM2上部的无活性结合拮抗剂的hA1AR结构和其余TM部分的结合激动剂的hA2AAR结构。这些与物种无关的A3AR选择性核苷是低效的部分激动剂和A3AR（一种日益受到关注的药物靶标）的新型细微调节剂。