(2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(4-nitro-phenoxycarbonyloxymethyl)-phenylcarbamoyloxy]-tetrahydro-pyran-2-carboxylic acid methyl ester | 799297-97-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(4-nitro-phenoxycarbonyloxymethyl)-phenylcarbamoyloxy]-tetrahydro-pyran-2-carboxylic acid methyl ester
• 英文别名: methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[[4-[(4-nitrophenoxy)carbonyloxymethyl]phenyl]carbamoyloxy]oxane-2-carboxylate
• CAS: 799297-97-5
• 化学式: C₂₈H₂₈N₂O₁₆
• 分子量: 648.534
• InChiKey: BUYBINGCLBCQOQ-LSHRBJLDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  46
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  234
• 氢给体数：
  1
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(4-nitro-phenoxycarbonyloxymethyl)-phenylcarbamoyloxy]-tetrahydro-pyran-2-carboxylic acid methyl ester 在 sodium methylate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 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：

  D-吡喃葡萄糖醛酸甲酯 1,2,3,4-四乙酸酯 在 吡啶 、 potassium hydrogensulfate 、 叠氮磷酸二苯酯 、 碳酸氢铵 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 水 、 甲苯 、 乙腈 为溶剂， 反应 9.0h， 生成 (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(4-nitro-phenoxycarbonyloxymethyl)-phenylcarbamoyloxy]-tetrahydro-pyran-2-carboxylic acid methyl ester
  参考文献：
  名称：

  [EN] POLYMERIC MICELLES COMPRISING GLUCURONIDE-PRODRUGS
  [FR] MICELLES POLYMÈRES COMPRENANT DES PROMÉDICAMENTS À BASE DE GLUCURONIDE

  摘要：

  该发明涉及一种聚合物胶束，包括一种嵌段共聚物，该嵌段共聚物包括一种聚乙二醇（PEG）亲水嵌段和一种疏水嵌段，并且包裹在该聚合物胶束内的化合物符合式（I）或式（III），以及其用途。

  公开号：

  WO2022008527A1

文献信息

• US8404650B2
  申请人：——

  公开号：US8404650B2

  公开（公告）日：2013-03-26