methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-(1-ethoxy-4-oxobutoxy)oxane-2-carboxylate | 197082-20-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-(1-ethoxy-4-oxobutoxy)oxane-2-carboxylate
• CAS: 197082-20-5
• 化学式: C₁₉H₂₈O₁₂
• 分子量: 448.424
• InChiKey: JGIAFWCZZRNADX-KVLLMYFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  31
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  150
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-(1-ethoxy-4-oxobutoxy)oxane-2-carboxylate 在 甲醇 、 sodium methylate 、 sodium cyanoborohydride 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 3.5h， 生成
  参考文献：
  名称：

  Intensely Cytotoxic Anthracycline Prodrugs:  Glucuronides

  摘要：

  We previously reported the synthesis of a series of doxorubicin analogue prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases. We now report studies on structurally related beta-glucuronide prodrugs that are converted to similar potent metabolites in the presence of beta-glucuronidases. These prodrugs were prepared by reductive condensation of daunomycin or doxorubicin with methyl 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2,3,4-tri-O-acetyl-beta-D-glucopyranosyluronate in the presence of sodium cyanoborohydride followed by base-mediated cleavage of the glucuronate protective groups. The doxorubicin derivatives were isolated in very low yield, most likely because of the inherent base lability of the parent aglycone. By contrast, fairly good yields of the more base-stable daunomycin analogues were obtained. The target daunomycin glucuronide, N-[(4''RS)-4''-ethoxy -4''-(sodium 1'''-O-beta-D-glucopyranuronate)butyl]daunorubicin (6a), bad a half-life of 30 h when incubated at a concentration of 12 mu M in aqueous 0.05 M phosphate buffer, pH 7.4, at 37 degrees C. Under identical conditions in the presence of 197 units/mu mol of Escherichia coli beta-glucuronidase, 6a was hydrolyzed with a half-life of 1.7 h. The single metabolite observed was chromatographically identical with that formed from the hydrolysis of N-(4,4-diacetoxybut-1-yl)daunomycin by carboxylate esterases. 6a was approximately 10000-fold more toxic to human A375 melanoma cells in the presence of E. coli beta-glucuronidase than in the absence of the enzyme. These findings indicate the therapeutic potential of anthracycline glucuronide prodrugs as independent entities or for use in conjunction with enzyme tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT).

  DOI：

  10.1021/jm970066d
• 作为产物：
  描述：

  (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-(1-ethoxy-pent-4-enyloxy)-tetrahydro-pyran-2-carboxylic acid methyl ester 在 二甲基硫 、 碳酸氢钠 、 臭氧 作用下， 生成 methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-(1-ethoxy-4-oxobutoxy)oxane-2-carboxylate
  参考文献：
  名称：

  Intensely Cytotoxic Anthracycline Prodrugs:  Glucuronides

  摘要：

  We previously reported the synthesis of a series of doxorubicin analogue prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases. We now report studies on structurally related beta-glucuronide prodrugs that are converted to similar potent metabolites in the presence of beta-glucuronidases. These prodrugs were prepared by reductive condensation of daunomycin or doxorubicin with methyl 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2,3,4-tri-O-acetyl-beta-D-glucopyranosyluronate in the presence of sodium cyanoborohydride followed by base-mediated cleavage of the glucuronate protective groups. The doxorubicin derivatives were isolated in very low yield, most likely because of the inherent base lability of the parent aglycone. By contrast, fairly good yields of the more base-stable daunomycin analogues were obtained. The target daunomycin glucuronide, N-[(4''RS)-4''-ethoxy -4''-(sodium 1'''-O-beta-D-glucopyranuronate)butyl]daunorubicin (6a), bad a half-life of 30 h when incubated at a concentration of 12 mu M in aqueous 0.05 M phosphate buffer, pH 7.4, at 37 degrees C. Under identical conditions in the presence of 197 units/mu mol of Escherichia coli beta-glucuronidase, 6a was hydrolyzed with a half-life of 1.7 h. The single metabolite observed was chromatographically identical with that formed from the hydrolysis of N-(4,4-diacetoxybut-1-yl)daunomycin by carboxylate esterases. 6a was approximately 10000-fold more toxic to human A375 melanoma cells in the presence of E. coli beta-glucuronidase than in the absence of the enzyme. These findings indicate the therapeutic potential of anthracycline glucuronide prodrugs as independent entities or for use in conjunction with enzyme tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT).

  DOI：

  10.1021/jm970066d