[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methyl 4-[[4-[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methoxy]-4-oxobutyl]disulfanyl]butanoate | 1215108-32-9

• 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: [(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methyl 4-[[4-[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methoxy]-4-oxobutyl]disulfanyl]butanoate
• CAS: 1215108-32-9
• 化学式: C₃₆H₄₆N₁₂O₄S₂
• 分子量: 774.971
• InChiKey: CHZBFHZFPOZWKN-PWGHIRGTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  54
• 可旋转键数：
  21
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  267
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  3-羧丙基二硫化物 、 阿巴卡韦 在 4-二甲氨基吡啶 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.33h， 以65%的产率得到[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methyl 4-[[4-[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methoxy]-4-oxobutyl]disulfanyl]butanoate
  参考文献：
  名称：

  Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood–Brain Barrier with Prodrug Abacavir Dimers

  摘要：

  Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.

  DOI：

  10.1021/ja206867t

文献信息

• Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood–Brain Barrier with Prodrug Abacavir Dimers
  作者：Hilda A. Namanja、Dana Emmert、David A. Davis、Christopher Campos、David S. Miller、Christine A. Hrycyna、Jean Chmielewski

  DOI：10.1021/ja206867t

  日期：2012.2.15

  Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.