6-chloro-9-((3aR,3bR,4aS,5R,5aS)-hexahydro-2,2dimethylbicyclo[3.1.0]hex-1(5)-eno[3,2-d] [1,3]dioxol-5-yl)-2-iodo-9H-purine | 1169605-26-8

• 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,3bR,4aS,5R,5aS)-hexahydro-2,2dimethylbicyclo[3.1.0]hex-1(5)-eno[3,2-d] [1,3]dioxol-5-yl)-2-iodo-9H-purine
• 英文别名: 6-chloro-9-((3aR,3bR,4aS,5R,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-iodo-9H-purine；(1'R,2'R,3'S,4'R,5'S)-4'-(6-chloro-2-iodopurine)-2',3'-O-isopropylidene-2',3'-dihydroxybicyclo[3.1.0]hexane；6-chloro-9-[(1R,2R,4S,5R,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]-2-iodopurine
• CAS: 1169605-26-8
• 化学式: C₁₄H₁₄ClIN₄O₂
• 分子量: 432.648
• InChiKey: GBAUTLZCVIMNEI-LUTUWXHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  62.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-chloro-9-((3aR,3bR,4aS,5R,5aS)-hexahydro-2,2dimethylbicyclo[3.1.0]hex-1(5)-eno[3,2-d] [1,3]dioxol-5-yl)-2-iodo-9H-purine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三氟甲磺酸 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 6.0h， 生成 (1R,2R,3S,4R,5S)-4-(6-((3-chlorophenethyl)amino)-2-((5-chlorothiophen-2-yl)ethynyl)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol
  参考文献：
  名称：

  小鼠和人类A3腺苷受体上的部分激动剂被截短的（N）-甲氨基甲酸酯核苷：通过N6-（2-苯基乙基）取代的亲和力增强。

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.0c00235
• 作为产物：
  描述：

  (3AS,4S,6AR)-2,2-二甲基-3A,6A-二氢-4H-环戊[D][1,3]二噁酚-4-醇 在 二碘甲烷 、 偶氮二甲酸二异丙酯 、 diethylzinc 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.25h， 生成 6-chloro-9-((3aR,3bR,4aS,5R,5aS)-hexahydro-2,2dimethylbicyclo[3.1.0]hex-1(5)-eno[3,2-d] [1,3]dioxol-5-yl)-2-iodo-9H-purine
  参考文献：
  名称：

  Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N⁶-Substituted-(N)-Methanocarba-nucleosides as A₃ Adenosine Receptor Antagonists and Partial Agonists

  摘要：

  Truncated N-6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N-6 and/or C2 substituents were tolerated in A(3)AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA(2A)AR affinity. A small hydrophobic alkyl (4b and 4c) or N-6-cycloalkyl group (4d) showed excellent binding affinity at the hA(3)AR and was better than an unsubstituted free amino group (4a). A(3)AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with K-i values of 7.8-16.0 nM. N-6-Methyl derivative 4b (K-i = 4.9 nM) was a highly selective, low efficacy partial A(3)AR agonist. All compounds were screened for renoprotective effects in human TGF-beta 1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-beta 1-induced collagen I upregulation, and their A(3)AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 mu M), indicating its potential as a good therapeutic candidate for treating renal fibrosis.

  DOI：

  10.1021/jm4015313

文献信息

• [EN] A3 ADENOSINE RECEPTOR AGONISTS FOR USE IN MEDICINE<br/>[FR] ANALOGUES DU RÉCEPTEUR A3 DE L'ADÉNOSINE POUR LE TRAITEMENT D'UNE MALADIE
  申请人：BIOINTERVENE INC

  公开号：WO2022040241A1

  公开（公告）日：2022-02-24

  The disclosure provides adenosine analogs for the treatment of disease such as pain and inflammatory conditions.

  该披露提供了用于治疗疾病如疼痛和炎症症状的腺苷类似物。
• Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System
  作者：Dilip K. Tosh、Moshe Chinn、Andrei A. Ivanov、Athena M. Klutz、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/jm900426g

  日期：2009.12.10

  (N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A3 adenosine receptor (AR) agonists (5′-uronamides) or antagonists (5′-truncated). Here, these two series were modified in parallel at the adenine C2 position. N6-3-Chlorobenzyl-5′-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating

  (N)-Methanocarba 核苷含有双环 [3.1.0] 己烷取代核糖环，先前证明选择性作为 A 3腺苷受体 (AR) 激动剂（5'-糖醛酰胺）或拮抗剂（5'-截短）。在这里，这两个系列在腺嘌呤 C2 位置并行修改。N 6 -3-Chlorobenzyl-5'- N - methyluronamides 衍生物具有不同长度的官能化 2-炔基链，末端为反应性羧酸盐、酯或胺基团，是完整的、有效的人类 A 3 AR 激动剂。链取代的灵活性允许与荧光花青染料 (Cy5) 和生物素结合，导致结合K i值分别为 17 和 36 nM。链的远端通过同源建模预测以结合在A 3 AR 细胞外区域。相应的l-核苷在 AR 结合中几乎没有活性。在 5'-截断的核苷系列中，2-Cl 类似物在 A 3 AR 上比 2-H 和 2-F 更有效，腺苷酸环化酶抑制的功能功效各不相同，2-炔基链的引入大大降低了亲和力。两个系列之间的
• Truncated Nucleosides as A₃ Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions
  作者：Dilip K. Tosh、Silvia Paoletta、Khai Phan、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/ml300107e

  日期：2012.7.12

  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.
• Rational Design of Sulfonated A₃Adenosine Receptor-Selective Nucleosides as Pharmacological Tools To Study Chronic Neuropathic Pain
  作者：Silvia Paoletta、Dilip K. Tosh、Amanda Finley、Elizabeth T. Gizewski、Steven M. Moss、Zhan-Guo Gao、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1021/jm4007966

  日期：2013.7.25

  (N)-Methanocarba(bicyclo[3.1.0]hexane)adenosine derivatives were probed for sites of charged sulfonate substitution, which precludes diffusion across biological membranes, e.g., blood-brain barrier. Molecular modeling predicted that sulfonate groups on C2-phenylethynyl substituents would provide high affinity at both mouse (m) and human (h) A(3) adenosine receptors (ARs), while a N-6-p-sulfophenylethyl substituent would determine higher hA(3)AR vs mA(3)AR affinity. These modeling predictions, based on steric fitting of the binding cavity and crucial interactions with key residues, were confirmed by binding/efficacy studies of synthesized sulfonates. N-6-3-Chlorobenzyl-2-(3-sulfophenylethynyl) derivative 7 (MRS5841) bound selectively to h/m A(3)ARs (K-i(hA(3)AR) = 1.9 nM) as agonist, while corresponding p-sulfo isomer 6 (MRS5701) displayed mixed A(1)/A(3)AR agonism. Both nucleosides administered ip reduced mouse chronic neuropathic pain that was ascribed to either A(3)AR or A(1)/A(3)AR using A(3)AR genetic deletion. Thus, rational design methods based on A(3)AR homology models successfully predicted sites for sulfonate incorporation, for delineating adenosine's CNS vs peripheral actions.
• Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity
  作者：Dilip K. Tosh、Silvia Paoletta、Francesca Deflorian、Khai Phan、Steven M. Moss、Zhan-Guo Gao、Xiaohui Jiang、Kenneth A. Jacobson

  DOI：10.1021/jm300965a

  日期：2012.9.27

  A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N-6-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N-6-dicyclopropylmethyl, K-i = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N-6-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N-6 suitable for an A(1)AR agonist with anticonvulsant activity.