ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-iodo-6-(methylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate | 1377273-14-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-iodo-6-(methylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate
• 英文别名: (1S,2R,3S,4R,5S)-ethyl-(2,3-O-isopropylidene)-4-(2-iodo-6-(methylamino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-1-carboxylate；ethyl (1R,2S,4S,5R,6S)-5-[2-iodo-6-(methylamino)purin-9-yl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxylate
• CAS: 1377273-14-7
• 化学式: C₁₈H₂₂IN₅O₄
• 分子量: 499.308
• InChiKey: MDACYOVQWBSJPM-DBNSSKNMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 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：

  ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-iodo-6-(methylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate 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 48.0h， 生成 (1S,2R,3S,4R,5S)-4-(2-((2-chlorophenyl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-O-isopropylidene-N-methylbicyclo[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 、 盐酸甲胺 在 三乙胺 作用下， 以 甲醇 为溶剂， 以94%的产率得到ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-iodo-6-(methylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate
  参考文献：
  名称：

  基于结构的设计、点击化学合成和高选择性 A3 腺苷受体激动剂的体内活性†

  摘要：

  ( 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

  DOI：

  10.1039/c4md00571f

文献信息

• Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters
  作者：Dilip K. Tosh、Aaron Janowsky、Amy J. Eshleman、Eugene Warnick、Zhan-Guo Gao、Zhoumou Chen、Elizabeth Gizewski、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1021/acs.jmedchem.7b00141

  日期：2017.4.13

  At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter transporter activity of rigid nucleosides

  我们重新调整了 (N)-methanocarba 腺苷衍生物（A3 腺苷受体 (AR) 激动剂）的用途，以增强放射性配体在人多巴胺 (DA) 转运蛋白 (DAT) 上的变构结合并抑制 DA 摄取。我们通过小N6-烷基取代、5'-酯、腺嘌呤的脱氮修饰以及恢复核糖代替甲烷碳，扩展了该系列的结构-活性关系。 C2-(5-卤代-2-基)-乙炔基 5'-甲基 9 (MRS7292) 和 5'-乙基 10 (MRS7232) 酯增强 DAT (EC50 ∼ 35 nM) 和去甲肾上腺素转运蛋白 (NET) 的结合。与 A3AR 相比，9 和 10 在小鼠中对 DAT 具有选择性，但在人类中则不然。在 DAT 中，两种结构不同的放射性配体的结合得到增强；仅一种放射性配体的 NET 结合得到增强； SERT 放射性配体结合受到的影响最小。 10 在抑制 DA 摄取方面比可卡因更有效 (IC50 = 107
• Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A₃ Receptor Agonists
  作者：Dilip K. Tosh、Veronica Salmaso、Harsha Rao、Ryan Campbell、Amelia Bitant、Zhan-Guo Gao、John A. Auchampach、Kenneth A. Jacobson

  DOI：10.1021/acsmedchemlett.9b00637

  日期：2020.10.8

  A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as A(3)AR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse A(3)AR. The mean affinity enhancement for 5 pairs of 5'-methylamides was 11-fold at hA(3)AR and 42-fold at mA(3)AR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hA(3)AR-selective 16 (MRS7334) displaying K-i 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of 16 and its corresponding riboside 8 suggested a qualitative entropic advantage of 16 in hA(3)AR binding. The 5-F substitution tended to increase hA(3)AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist 4 was shown to interact potently exclusively with A(3)AR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for A(3)AR agonists, which have translational potential for chronic disease treatment.