N-[4-(doxorubicin-N-carbonyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucuronyl) carbamate | 186653-67-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: N-[4-(doxorubicin-N-carbonyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucuronyl) carbamate
• CAS: 186653-67-8
• 化学式: C₄₉H₅₂N₂O₂₄
• 分子量: 1052.95
• InChiKey: WCHZCYXCMGCXIW-RMVSQZJOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.21
• 重原子数：
  75.0
• 可旋转键数：
  14.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  371.14
• 氢给体数：
  7.0
• 氢受体数：
  24.0

反应信息

• 作为反应物：
  描述：

  N-[4-(doxorubicin-N-carbonyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucuronyl) carbamate 在 sodium methylate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 1.0h， 生成 N-[4-(doxorubicin-N-carbonyloxymethyl)phenyl] O-(methyl-O-β-glucuronyl) carbamate
  参考文献：
  名称：

  A methylester of the glucuronide prodrug DOX-GA3 for improvement of tumor-selective chemotherapy

  摘要：

  The glucuronide prodrug of doxorubicin, DOX-GA3, can be selectively activated in tumors by extracellular human P-glucuronidase, resulting in a better therapeutic index than doxorubicin. DOX-GA3, however, is rapidly excreted by the kidney. We hypothesized that slow release of DOX-GA3 from its methylester, DOX-mGA3, by esterase activity in blood would result in improved circulation half-life (t(1/2)) of DOX-GA3. DOX-mGA3 was synthesized more efficiently with an overall yield of 60% as compared to 37% in the case of DOX-GA3. We showed that DOX-mGA3 was enzymatically converted to DOX-GA3 with a t(1/2) of approximately 0.5 min in mouse plasma to 2.5 h in human plasma, which was in agreement with differences in esterase activity between species. DOX-mGA3, similar to DOX-GA3, was at least 37-fold less potent than the parent drug doxorubicin in growth inhibition of four different human malignant cell lines in vitro. Incubation of OVCAR-3 cells with DOX-mGA3 in combination with an excess of human P-glucuronidase (0.05 U mL(-1)) resulted in a similar growth inhibition to that of doxorubicin. Intravenous administration of DOX-mGA3 in FMa-bearing mice resulted in an area under the concentration versus time curve (AUC) of DOX-GA3 in tumor and most normal tissues that was 2.5- to 3-fold higher than after the same dose of DOX-GA3 itself In tumor tissue, this was accompanied by a 2.7-fold increase in the AUC of doxorubicin from DOX-mGA3 than from DOX-GA3. In conclusion, an advantage of DOX-mGA3 over DOX-GA3 is that this prodrug can be produced with a higher yield. Another important advantage is the improved pharmacokinetics of the lipophilic DOX-mGA3 as compared to that of the hydrophilic DOX-GA3. This effect may even be more pronounced in man, because of the lower plasma esterase activity than measured in mice. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2004.08.004
• 作为产物：
  描述：

  2,3,4-Tri-O-acetyl-β-D-glucopyranuronic acid methylester 在 吡啶 、 二苯基磷酸 、 水 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 N-[4-(doxorubicin-N-carbonyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucuronyl) carbamate
  参考文献：
  名称：

  A methylester of the glucuronide prodrug DOX-GA3 for improvement of tumor-selective chemotherapy

  摘要：

  The glucuronide prodrug of doxorubicin, DOX-GA3, can be selectively activated in tumors by extracellular human P-glucuronidase, resulting in a better therapeutic index than doxorubicin. DOX-GA3, however, is rapidly excreted by the kidney. We hypothesized that slow release of DOX-GA3 from its methylester, DOX-mGA3, by esterase activity in blood would result in improved circulation half-life (t(1/2)) of DOX-GA3. DOX-mGA3 was synthesized more efficiently with an overall yield of 60% as compared to 37% in the case of DOX-GA3. We showed that DOX-mGA3 was enzymatically converted to DOX-GA3 with a t(1/2) of approximately 0.5 min in mouse plasma to 2.5 h in human plasma, which was in agreement with differences in esterase activity between species. DOX-mGA3, similar to DOX-GA3, was at least 37-fold less potent than the parent drug doxorubicin in growth inhibition of four different human malignant cell lines in vitro. Incubation of OVCAR-3 cells with DOX-mGA3 in combination with an excess of human P-glucuronidase (0.05 U mL(-1)) resulted in a similar growth inhibition to that of doxorubicin. Intravenous administration of DOX-mGA3 in FMa-bearing mice resulted in an area under the concentration versus time curve (AUC) of DOX-GA3 in tumor and most normal tissues that was 2.5- to 3-fold higher than after the same dose of DOX-GA3 itself In tumor tissue, this was accompanied by a 2.7-fold increase in the AUC of doxorubicin from DOX-mGA3 than from DOX-GA3. In conclusion, an advantage of DOX-mGA3 over DOX-GA3 is that this prodrug can be produced with a higher yield. Another important advantage is the improved pharmacokinetics of the lipophilic DOX-mGA3 as compared to that of the hydrophilic DOX-GA3. This effect may even be more pronounced in man, because of the lower plasma esterase activity than measured in mice. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2004.08.004

文献信息

• Novel anthracycline-spacer-β-glucuronide, -β-glucoside, and -β-galactoside prodrugs for application in selective chemotherapy
  作者：Ruben G.G. Leenders、Eric W.P. Damen、Edward J.A. Bijsterveld、Hans W. Scheeren、Pieter H.J. Houba、Ida H. van der Meulen-Muileman、Epie Boven、Hidde J. Haisma

  DOI：10.1016/s0968-0896(99)00095-4

  日期：1999.8

  A series of anthracycline prodrugs containing an immolative spacer was synthesized for application in selective chemotherapy. The prodrugs having the general structure anthracycline-spacer-beta-glycoside were designed to be activated by beta-glucuronidase or beta-galactosidase. Prodrugs with -chloro, bromo or -n-hexyl substituents on the spacer were synthesized as well as prodrugs containing a -beta-glucuronyl, -beta-glucosyl or -beta-galactosyl carbamate specifier. The key step in the synthesis of all prodrugs is the highly beta-diastereoselective addition reaction of the anomeric hydroxyl of a glycosyl donor to a spacer isocyanate resulting in the respective beta-glycosyl carbamate pro-moieties. The resulting protected pro-moieties were coupled to an anthracycline. Prodrugs were evaluated with respect to activation rate by the appropriate enzyme and additionally, their IC50 values were determined. Optimal prodrugs in this study were at least 100- to 200-fold less toxic than their corresponding drug in vitro and were activated to the parent drug in a half-life time of approximately 2 h. (C) 1999 Elsevier Science Ltd. All rights reserved.