N-[4-(t-butyldimethylsilyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranuronosyl) carbamate | 184579-83-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-[4-(t-butyldimethylsilyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranuronosyl) carbamate
• 英文别名: methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]carbamoyloxy]oxane-2-carboxylate
• CAS: 184579-83-7
• 化学式: C₂₇H₃₉NO₁₂Si
• 分子量: 597.692
• InChiKey: PNMKVASCUACVPF-WHGMEAMLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.45
• 重原子数：
  41
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  162
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N-[4-(t-butyldimethylsilyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranuronosyl) carbamate 在 吡啶 、 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 21.0h， 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
• 作为产物：
  描述：

  4-[(叔丁基二甲基甲硅烷基氧基)甲基]苯甲酸 在 二苯基膦叠氮化物 、 三乙胺 作用下， 以 甲苯 为溶剂， 反应 2.0h， 生成 N-[4-(t-butyldimethylsilyloxymethyl)phenyl] O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranuronosyl) carbamate
  参考文献：
  名称：

  Highly Diastereoselective Synthesis of Anomeric β-O-Glycopyranosyl Carbamates from Isocyanates

  摘要：

  1-β-O-Glycopyranosyl carbamates 是通过在几乎 100% β-对映选择性下，从无保护的α-糖苷和异氰酸酯制备的。异氰酸酯则是由羧酸通过酰基叠氮化物原位制备得来的。

  DOI：

  10.1055/s-1996-4377

文献信息

• [EN] POLYMERIC MICELLES COMPRISING GLUCURONIDE-PRODRUGS<br/>[FR] MICELLES POLYMÈRES COMPRENANT DES PROMÉDICAMENTS À BASE DE GLUCURONIDE
  申请人：RWTH AACHEN

  公开号：WO2022008527A1

  公开（公告）日：2022-01-13

  The invention relates to a polymeric micelle comprising a block copolymer comprising a polyethylene glycol (PEG) hydrophilic block and a hydrophobic block, and a compound according to formula (I) or formula (III) encapsulated within said polymeric micelle and to uses thereof.

  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。
• 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.