(1S,2R,3S,4S,5S)-1-[diisopropyl-phosphonoethyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane | 1215320-38-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物
• 英文名称: (1S,2R,3S,4S,5S)-1-[diisopropyl-phosphonoethyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane
• 英文别名: (1R,2S,4S,5S,6S)-2-[2-di(propan-2-yloxy)phosphorylethyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol
• CAS: 1215320-38-9
• 化学式: C₁₇H₃₁O₆P
• 分子量: 362.403
• InChiKey: MEPBZIVYIDPYHK-JLHDYFKBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  74.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1S,2R,3S,4S,5S)-1-[diisopropyl-phosphonoethyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane 在 甲醇 、 偶氮二甲酸二异丙酯 、 氨 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 55.67h， 生成 diisopropyl (2-((3aR,3bS,4aS,5R,5aS)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethyl)phosphonate
  参考文献：
  名称：

  Synthesis and P2Y2 receptor agonist activities of uridine 5′-phosphonate analogues

  摘要：

  We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl) methylidene] triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.02.012
• 作为产物：
  描述：

  (1R,2R,3S,4S,5S)-1-(叔-丁基二苯基)硅烷基氧基甲基-2,3-二氧基-O,O-异亚丙基双环[3.1.0]己烷-4-醇 在 正丁基锂 、 palladium on activated charcoal 、 四丁基氟化铵 、 氢气 、 sodium hydride 、 戴斯-马丁氧化剂 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 44.0h， 生成 (1S,2R,3S,4S,5S)-1-[diisopropyl-phosphonoethyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives

  摘要：

  越来越多的证据表明，嘌呤能信号传导在心脏疾病中发挥着治疗作用。此前，在心力衰竭动物模型中证实了全身灌注 MRS2339（2-Cl-腺苷单磷酸的带电甲氧羰基衍生物）的疗效。现在，我们对以下假设进行了验证：一种不带电的腺嘌呤核苷膦酸盐，适合作为具有抗水解磷酸分子的口服药物，可在梗死后缺血或压力过载诱导的小鼠心力衰竭模型中预防心功能不全的发生。在缺血或压力过载诱导的心力衰竭开始时，口服二酯掩蔽的非带电膦酸盐 MRS2978 能有效预防心功能不全，并能改善左心室（LV）分数缩短率。MRS2925是一种带电、未掩蔽的MRS2978类似物，皮下注射可预防心功能不全，但口服则无效。口服或全身给药时，MRS2978（而非 MRS2925）也能挽救缺血和压力过载心力衰竭模型中已建立的心功能障碍。二酯掩蔽磷酸盐 MRS4074 在预防功能障碍的发生以及挽救压力过载引起的心衰和缺血性心衰方面具有很高的疗效。在大鼠试验中，MRS2978 的口服生物利用度高（57-75%），在体内可产生次要代谢产物 MRS2925。这些数据表明腺嘌呤核苷膦酸盐对收缩性心力衰竭具有新的治疗作用。

  DOI：

  10.1007/s11302-020-09688-0

文献信息

• Structure−Activity Relationship of (<i>N</i>)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor
  作者：T. Santhosh Kumar、Si-Yuan Zhou、Bhalchandra V. Joshi、Ramachandran Balasubramanian、Tiehong Yang、Bruce T. Liang、Kenneth A. Jacobson

  DOI：10.1021/jm9018542

  日期：2010.3.25

  P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3',5,4'R,5'S)-4'-(6-amino-2-chloropurin-9-y1)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.