4-aminophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranoside | 1001407-04-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-aminophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranoside
• 英文别名: [(2R,3R,4S,5R,6S)-3,4-diacetyloxy-6-(4-aminophenoxy)-5-fluorooxan-2-yl]methyl acetate
• CAS: 1001407-04-0
• 化学式: C₁₈H₂₂FNO₈
• 分子量: 399.373
• InChiKey: VZQLNPHZBYDPDT-DUQPFJRNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  123
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-aminophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranoside 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 65.0h， 生成 N-{2-[4-(3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranosyloxy)phenyl]amino-2-oxoethyl}-4-{4-[bis(2-chloroethyl)amino]phenyl}butanamide
  参考文献：
  名称：

  Conjugates of 2-fluoro-2-deoxy-glucose and their uses as anti cancer agents

  摘要：

  本发明涉及一般式（I）的化合物：其中：- R1、R2和R3分别独立地表示氢原子或可选择取代的较低烷基，（C1-C7）酰基团或苄基，- R4是可选择取代和/或中断的碳氢链，- X和Y分别独立地从-NH-，-NR'-，-CO-，-NH（CO）-，-NH（CO）NH-，-NR'（CO）-，-O（CO）NH-，-O（CO）NR'-，-（CO）NH-，-（CO）NR'-，-NH（CO）（R"）NH（CO）-，-（CO）NH（R"（CO）NH-，-O-，-（CO）O-，-NH（CO）O-，-SC（O）NH-，-NHSO2-，-NR'SO2-和-O（CO）-中选择，并且最好彼此不同，其中R'是可选择取代的较低烷基团，R"是（C1-C3）烷基，- Z基团代表抗肿瘤剂，- n表示0或1，- 及其药用盐。还涉及将这些化合物用作抗癌剂。

  公开号：

  EP1881000A1
• 作为产物：
  描述：

  3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-α-D-glucopyranosyl bromide 在 palladium 10% on activated carbon 氢气 、 silver(l) oxide 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 反应 46.0h， 生成 4-aminophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranoside
  参考文献：
  名称：

  Conjugates of 2-fluoro-2-deoxy-glucose and their uses as anti cancer agents

  摘要：

  本发明涉及一般式（I）的化合物：其中：- R1、R2和R3分别独立地表示氢原子或可选择取代的较低烷基，（C1-C7）酰基团或苄基，- R4是可选择取代和/或中断的碳氢链，- X和Y分别独立地从-NH-，-NR'-，-CO-，-NH（CO）-，-NH（CO）NH-，-NR'（CO）-，-O（CO）NH-，-O（CO）NR'-，-（CO）NH-，-（CO）NR'-，-NH（CO）（R"）NH（CO）-，-（CO）NH（R"（CO）NH-，-O-，-（CO）O-，-NH（CO）O-，-SC（O）NH-，-NHSO2-，-NR'SO2-和-O（CO）-中选择，并且最好彼此不同，其中R'是可选择取代的较低烷基团，R"是（C1-C3）烷基，- Z基团代表抗肿瘤剂，- n表示0或1，- 及其药用盐。还涉及将这些化合物用作抗癌剂。

  公开号：

  EP1881000A1

文献信息

• Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy
  作者：Mostafa El Hilali、Bastien Reux、Eric Debiton、Fernand Leal、Marie-Josephe Galmier、Magali Vivier、Jean-Michel Chezal、Elisabeth Miot-Noirault、Pascal Coudert、Valérie Weber

  DOI：10.1016/j.bmc.2017.08.043

  日期：2017.10

  glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human tumor cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to

  氮芥，例如苯丁酸氮芥（CLB），由于在非目标器官中普遍分布而可能引起不利的副作用。为了最小化这种毒性，已经开发了靶向肿瘤的药物递送策略，其中细胞毒性弹头与肿瘤细胞特异性小配体相连。恶性细胞通过有氧糖酵解表现出明显的葡萄糖亲和力和加速的代谢，这被称为Warburg效应，被认为是癌症的标志。先前已经报道了一种通过将CLB与2-氟-2-脱氧葡萄糖（FDG）结合来利用Warburg效应的靶向方法，并确定了两种在体内具有有希望的抗肿瘤活性的过乙酰化葡萄糖结合物2和3 。。这些结果促使我们研究间隔子在这种靶向肿瘤的基于葡萄糖的结合物中的重要性。在这里，我们报告了16种新的CLB葡萄糖缀合物的化学合成和体外细胞毒性评估，该评估是使用人类肿瘤细胞系和人类成纤维细胞的5人小组进行的，其中烷基化药物通过不同的方式连接到FDG的C-1位置联系。我们研究了接头中的结构-活性关系，并证明了芳香族接头对体外细胞毒性的
• Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs
  作者：Pierre Daumar、Caroline Decombat、Jean-Michel Chezal、Eric Debiton、Michel Madesclaire、Pascal Coudert、Marie-Josèphe Galmier

  DOI：10.1016/j.ejmech.2011.04.010

  日期：2011.7

  In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling (2a) or via various spacers (3, 6a-c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 degrees C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a-c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently. (C) 2011 Elsevier Masson SAS. All rights reserved.
• Synthesis and cytotoxic properties of new fluorodeoxyglucose-coupled chlorambucil derivatives
  作者：Bastien Reux、Valérie Weber、Marie-Josephe Galmier、Michèle Borel、Michel Madesclaire、Jean-Claude Madelmont、Eric Debiton、Pascal Coudert

  DOI：10.1016/j.bmc.2008.03.038

  日期：2008.5

  Frequently used in the treatment of malignant cells, alkylating agents, like most anticancer substances, produce adverse side effects caused by the toxicity of the agents toward normal tissues and lose efficiency through poor distribution to target sites. Our approach to developing more selective drugs with low systemic toxicity is based on the premise that the body distribution and cell uptake of a drug can be altered by attaching a neoplastic cell-specific uptake enhancer, such as 2-fluoro-2-deoxyglucose (FDG), the radiotracer most frequently used in PET for tumor imaging. Two properties of deoxyglucose, namely preferential accumulation in neoplastic cells and inhibition of glycolysis, underpin this targeting approach. Here, we report the synthesis of 19 new chlorambucil glycoconjugates in which the alkylating drug is attached to the C-1 position of FDG, directly or via different linkages. This set of compounds was evaluated for in vitro cytotoxicity against different human normal and tumor cell lines. There was a significant improvement in the in vitro cytotoxicity of peracetylated glucoconjugates compared with the free substance. Four compounds were finally selected for further in vivo studies owing to their lack of oxidative stress-inducing properties. (c) 2008 Elsevier Ltd. All rights reserved.