(1'S,2'R,3'S,4'R,5'S)-4'-(6-chloropurin-9-yl)-1'-[diisopropyl-(E)-phosphonoethenyl]-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane | 1215320-35-6

• 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-chloropurin-9-yl)-1'-[diisopropyl-(E)-phosphonoethenyl]-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane
• 英文别名: 6-chloro-9-[(1R,2R,4S,5R,6S)-2-[(E)-2-di(propan-2-yloxy)phosphorylethenyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]purine
• CAS: 1215320-35-6
• 化学式: C₂₂H₃₀ClN₄O₅P
• 分子量: 496.931
• InChiKey: RRBCFKREBGEAGB-WCLVXEFESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  97.6
• 氢给体数：
  0
• 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-chloropurin-9-yl)-1'-[diisopropyl-(E)-phosphonoethenyl]-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane 在 氨 作用下， 以 异丙醇 为溶剂， 反应 17.0h， 以85%的产率得到(1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-1'-[diisopropyl-(E)-ethenylphosphonate]-2',3'-O-(isopropylidine)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Structure−Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor

  摘要：

  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.

  DOI：

  10.1021/jm9018542
• 作为产物：
  描述：

  6-氯嘌呤 、 (1S,2R,3S,4S,5S)-1-[diisopropyl-(E)-phosphonoethenyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 60.5h， 以85%的产率得到(1'S,2'R,3'S,4'R,5'S)-4'-(6-chloropurin-9-yl)-1'-[diisopropyl-(E)-phosphonoethenyl]-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Structure−Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor

  摘要：

  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.

  DOI：

  10.1021/jm9018542

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.