(-)-6-chloro-9-((3aR,6R,6aR)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)-9H-purine | 1166277-84-4

• 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: (-)-6-chloro-9-((3aR,6R,6aR)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)-9H-purine
• 英文别名: 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine
• CAS: 1166277-84-4
• 化学式: C₁₂H₁₃ClN₄O₃
• 分子量: 296.713
• InChiKey: DBZSIOKVHHXAMI-AZTOOPQRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.53
• 重原子数：
  20.0
• 可旋转键数：
  1.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  71.29
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (-)-6-chloro-9-((3aR,6R,6aR)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)-9H-purine 在 2,2,6,6-四甲基哌啶 、 盐酸 、 copper(l) iodide 、 四(三苯基膦)钯 、 正丁基锂 、 碘 、 caesium carbonate 作用下， 以 四氢呋喃 、 正己烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 43.5h， 生成 (-)-(2R,3R,4R)-2-(6-chloro-2-(hex-1-ynyl)-9H-purin-9-yl)-tetrahydrofuran-3,4-diol
  参考文献：
  名称：

  Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

  摘要：

  Truncated N-6-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)ARdocking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

  DOI：

  10.1021/jm201229j
• 作为产物：
  描述：

  2,3-O-亚异丙基赤藓糖 在 吡啶 、 硫酸氢铵 、 六甲基二硅氮烷 作用下， 反应 18.5h， 生成 (-)-6-chloro-9-((3aR,6R,6aR)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)-9H-purine
  参考文献：
  名称：

  GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A_2A Adenosine Receptor

  摘要：

  DOI：

  10.1021/acs.jmedchem.2c00462

文献信息

• Structure–Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A_2A/A₃ Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity
  作者：Gibae Kim、Xiyan Hou、Woong Sub Byun、Gyudong Kim、Dnyandev B. Jarhad、Grim Lee、Young Eum Hyun、Jinha Yu、Chang Soo Lee、Shuhao Qu、Eugene Warnick、Zhan-Guo Gao、Ji Yong Kim、Seunghee Ji、Hyunwoo Shin、Jong-Ryoul Choi、Kenneth A. Jacobson、Hyuk Woo Lee、Sang Kook Lee、Lak Shin Jeong

  DOI：10.1021/acs.jmedchem.3c00806

  日期：2023.9.14

  hA2AAR structures, a hydrophobic C8-heteroaromatic ring in 5′-truncated adenosine analogues occupies the subpocket tightly, converting hA2AAR agonists into antagonists while maintaining affinity toward hA3AR. The final compounds of 2,8-disubstituted-N6-substituted 4′-thionucleosides, or 4′-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled

  基于hA 2A AR结构，5'-截短腺苷类似物中的疏水性C8-杂芳环紧密占据亚袋，将hA 2A AR激动剂转化为拮抗剂，同时保持对hA 3 AR的亲和力。使用 Pd 催化剂，分别从d-甘露糖和d-赤酮-1,4-内酯合成 2,8-二取代-N 6 -取代的 4'-硫代核苷或 4'-氧代的最终化合物。受控的区域选择性交叉偶联反应。所有测试的化合物均完全拮抗 hA 2A AR，包括5d时具有最高亲和力 ( K i,A 2A = 7.7 ± 0.5 nM)。 hA 2A AR– 5d X 射线结构表明，C8 杂芳环可阻止受体激活相关的构象变化。然而，C8取代的化合物仍然拮抗hA 3 AR。结构 SAR 特征和对接研究支持 A 2A AR 和 A 3 AR 的不同结合模式，阐明了受体激活和选择性的药效团。证明了良好的药代动力学，其中5d表现出高口服吸收、中等半衰期和生物利用度。而且， 5d后抗PD-L
• Structure–activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists
  作者：Shantanu Pal、Won Jun Choi、Seung Ah Choe、Cara L. Heller、Zhan-Guo Gao、Moshe Chinn、Kenneth A. Jacobson、Xiyan Hou、Sang Kook Lee、Hea Ok Kim、Lak Shin Jeong

  DOI：10.1016/j.bmc.2009.03.034

  日期：2009.5

  On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N-6 positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K-i = 13.0 +/- 6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development. (C) 2009 Elsevier Ltd. All rights reserved.