(3aS,3bS,4aS,5R,5aS)-5-(6-((3-chlorobenzyl)amino)-2-((3-chlorophenyl)ethynyl)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide | 1377273-63-6

• 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: (3aS,3bS,4aS,5R,5aS)-5-(6-((3-chlorobenzyl)amino)-2-((3-chlorophenyl)ethynyl)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide
• CAS: 1377273-63-6
• 化学式: C₃₁H₂₈Cl₂N₆O₃
• 分子量: 603.508
• InChiKey: AKNXUPLAVSXWKE-AKIWZWGDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.97
• 重原子数：
  42.0
• 可旋转键数：
  5.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  103.19
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (3aS,3bS,4aS,5R,5aS)-5-(6-((3-chlorobenzyl)amino)-2-((3-chlorophenyl)ethynyl)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide 以 甲醇 为溶剂， 反应 5.0h， 生成 (1S,2R,3S,4R,5S)-4-(6-(3-chlorobenzylamino)-2-((3-chlorophenyl)ethynyl)-9H-purin-9-yl)-2,3-dihydroxy-N-Nmethylbicyclo[3.1.0]hexane-1-carboxamide
  参考文献：
  名称：

  Structure-Guided Design of A₃ Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions

  摘要：

  (N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)enhancing modifications, i.e., 2-(arylethynyl)adenine and N-6-methyl or N-6-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K-i similar to 0.6 nM, N-6-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N-6-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K-i 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N-6-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K-i hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K-i hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR. agonists.

  DOI：

  10.1021/jm300396n
• 作为产物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4'-[6-chloro-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3aS,3bS,4aS,5R,5aS)-5-(6-((3-chlorobenzyl)amino)-2-((3-chlorophenyl)ethynyl)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide
  参考文献：
  名称：

  Structure-Guided Design of A₃ Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions

  摘要：

  (N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)enhancing modifications, i.e., 2-(arylethynyl)adenine and N-6-methyl or N-6-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K-i similar to 0.6 nM, N-6-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N-6-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K-i 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N-6-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K-i hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K-i hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR. agonists.

  DOI：

  10.1021/jm300396n