(1'S,2'R,3'S,4'R,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester | 793695-83-7

• 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: (1'S,2'R,3'S,4'R,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester
• 英文别名: (1'S,2'R,3'S,4'S,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodo-purin-9-yl]-2',3'-O-isopropylidene-bicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester；ethyl (1R,2S,4S,5R,6S)-5-[6-[(3-chlorophenyl)methylamino]-2-iodopurin-9-yl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxylate
• CAS: 793695-83-7
• 化学式: C₂₄H₂₅ClIN₅O₄
• 分子量: 609.851
• InChiKey: CFUKDEQGDGIZGV-WMNHRYSVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4'-[6-(3-chlorobenzylamino)-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， 反应 5.0h， 生成 (1S，2R，3S，4R，5S)-4-[6-[[((3-氯苯基)甲基]氨基]-2-[2-(3,4-二氟苯基)乙炔基]-9H-嘌呤-9-yl]-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-羧酰胺
  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：

  乙基(1S,2R,3S,4S,5S)-2,3-O-(异亚丙基)-4-羟基双环[3.1.0]己烷羧酸酯 在 偶氮二甲酸二异丙酯 、 TEA 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 10.0h， 生成 (1'S,2'R,3'S,4'R,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester
  参考文献：
  名称：

  (N)-Methanocarba 2,N⁶-Disubstituted Adenine Nucleosides as Highly Potent and Selective A₃ Adenosine Receptor Agonists

  摘要：

  A series of ring-constrained (N)-methanocarba-5 '-uronamide 2,N-6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5 '-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5 '-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A(3)AR agonists. Selected compounds were compared in binding to the rat A(3)AR to assess their viability for testing in rat disease models. The N-6-(3-chlorobenzyl) and N-6-(3-bromobenzyl) analogues displayed K-i values at the human A(3)AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N-6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A(3)AR was the following (fold): the N-6-(2,2-diphenylethyl) analogue 34 (1900), the N-6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N-6-(2,5-dichlorobenzyl) and N-6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N-6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A(2A) and A(2B)ARs. The (N)-methanocarba-5 '-uronamide analogues were full agonists at the A(3)AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 mu M. The N-6-(2,2-diphenylethyl) derivative was an A(3)AR agonist in the (N)-methanocarba-5 '-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.

  DOI：

  10.1021/jm049580r

文献信息

• Structure-based design, synthesis by click chemistry and <i>in vivo</i> activity of highly selective A₃ adenosine receptor agonists
  作者：Dilip K. Tosh、Silvia Paoletta、Zhoumou Chen、Steven Crane、John Lloyd、Zhan-Guo Gao、Elizabeth T. Gizewski、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1039/c4md00571f

  日期：——

  2-Arylethynyl derivatives of (N)-methanocarba adenosine 5′-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based

  ( N )-methanocarba 腺苷 5'-uronamides 的 2-芳基乙炔基衍生物是选择性 A 3 AR（腺苷受体）激动剂。在这里，我们用 1,2,3-三唑-1-基连接体代替刚性的线性乙炔基，以消除其潜在的代谢负担。使用 A 3 AR的混合分子模型（基于 A 2A AR 激动剂结合结构）将含有可能的短连接体部分的核苷对接在腺嘌呤 C2 位置，正确预测三唑将保持 A 3 AR 选择性，因为它能够适应受体中的狭窄裂缝。合成了具有各种N 6和 C2-芳基三唑基取代的类似物，并对其结合（ K i at hA 3 AR 0.3–12 nM）和体内特征进行了表征，以证明控制慢性神经性疼痛（慢性缩窄性损伤）的功效。在N 6 -甲基衍生物中， 9 (MRS7116)中的末端嘧啶-2-基基团增加了体内作用持续时间（3 小时时疼痛保护 36%）。N 6 -乙基 5-氯噻吩-2-基类似物15 (M
• 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.