5'-O-<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-didehydro-2',3'-dideoxythymidine | 118869-95-7

• 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: 5'-O-<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-didehydro-2',3'-dideoxythymidine
• 英文别名: 5'-O-[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]-2',3'-didehydro-2',3'-dideoxythymidine；[(2s,5r)-5-(5-Methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methyl 1-methyl-4h-pyridine-3-carboxylate；[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methyl 1-methyl-4H-pyridine-3-carboxylate
• CAS: 118869-95-7
• 化学式: C₁₇H₁₉N₃O₅
• 分子量: 345.355
• InChiKey: FDGMLYWKDUYVBL-UONOGXRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  88.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5'-O-<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-didehydro-2',3'-dideoxythymidine 在 双氧水 作用下， 生成 5'-O-(1''-methyl-3''-pyridiniocarbonyl)-2',3'-didehydro-2',3'-dideoxythymidine
  参考文献：
  名称：

  A dihydropyridine carrier system for sustained delivery of 2',3'-dideoxynucleosides to the brain

  摘要：

  The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.

  DOI：

  10.1021/jm00123a020
• 作为产物：
  描述：

  司他夫定 在 吡啶 、 4-二甲氨基吡啶 、 sodium dithionite 、 碳酸氢钠 作用下， 以 甲醇 、 水 、 丙酮 为溶剂， 反应 66.33h， 生成 5'-O-<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-didehydro-2',3'-dideoxythymidine
  参考文献：
  名称：

  A dihydropyridine carrier system for sustained delivery of 2',3'-dideoxynucleosides to the brain

  摘要：

  The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.

  DOI：

  10.1021/jm00123a020

文献信息

• PALOMINO, EDUARDO;KESSEL, DAVID;HORWITZ, JEROME P., J. MED. CHEM., 32,(1989) N, C. 622-625
  作者：PALOMINO, EDUARDO、KESSEL, DAVID、HORWITZ, JEROME P.

  DOI：——

  日期：——
• A dihydropyridine carrier system for sustained delivery of 2',3'-dideoxynucleosides to the brain
  作者：Eduardo Palomino、David Kessel、Jerome P. Horwitz

  DOI：10.1021/jm00123a020

  日期：1989.3

  The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.