1-O-(2-甲酰基-4-硝基苯基)-2,3,4-三-O-乙酰基-β-D-吡喃葡萄糖醛酸甲酯 | 148579-83-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 1-O-(2-甲酰基-4-硝基苯基)-2,3,4-三-O-乙酰基-β-D-吡喃葡萄糖醛酸甲酯
• 英文名称: (2S,3R,4S,5S,6S)-2-(2-formyl-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
• 英文别名: methyl 1-O-(2-formyl-4-nitrophenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate；Methyl 1-O-(2-Formyl-4-nitrophenyl)-2,3,4-tri-O-acetyl-beta-D-glucopyranuronate；methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-(2-formyl-4-nitrophenoxy)oxane-2-carboxylate
• CAS: 148579-83-3
• 化学式: C₂₀H₂₁NO₁₃
• 分子量: 483.386
• InChiKey: LPLDMUGULFEJJK-KVIJGQROSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  187
• 氢给体数：
  0
• 氢受体数：
  13

安全信息

• 储存条件：
  储存条件：2-8°C，需使用惰性气体保存。

反应信息

• 作为反应物：
  描述：

  1-O-(2-甲酰基-4-硝基苯基)-2,3,4-三-O-乙酰基-β-D-吡喃葡萄糖醛酸甲酯 在 甲醇 、 二乙胺基三氟化硫 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 20.0~70.0 ℃ 、182.4 kPa 条件下， 反应 42.0h， 生成 1-O-(2-difluoromethyl-4-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl))acetamido)phenyl)-β-D-glucopyranuronate
  参考文献：
  名称：

  Development of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for β-Glucuronidase Activity Profiling

  摘要：

  beta-Glucuronidase is a key lysosomal enzyme and is often overexpressed in necrotic tumor masses. We report here the synthesis of a pro receptor induced magnetization enhancement (pro RIME) magnetic resonance imaging (MRI) contrast agent ([Gd(DOTA-FP beta Gu)]) for molecular imaging of beta-glucuronidase activity in tumor tissues. The contrast agent consists of two parts, a gadolinium complex and a beta-glucuronidase substrate (beta-D-glucopyranuronic acid). The binding association constant (K-A) of [Gd(DOTA-FP beta Gu)] is 7.42 X 10(2), which is significantly lower than that of a commercially available MS-325 (K-A = 3.0 x 10(4)) RIME contrast agent. The low K-A value of [Gd(DOTA-FP beta Gu)] is due to the pendant beta-D-glucopyranuronic acid moiety. Therefore, [Gd(DOTA-FP beta Gu)] can be used for detection of beta-glucuronidase through RIME modulation. The detail mechanism of enzymatic activation of [Gd(DOTA-FP beta Gu)] was elucidated by LC-MS. The kinetics of beta-glucuronidase catalyzed hydrolysis of [Eu(DOTA-FP beta Gu)] at pH 7.4 best fit the Miechalis-Menten kinetic mode with K-m = 1.38 mM, K-cat = 3.76 x 10(3), and k(cat)/K-m = 2.72 x 10(3) M-1 s(-1). The low K-m value indicates high affinity of beta-glucuronidase for [Gd(DOTA-FP beta Gu)] FP beta Gu) at physiological pH. Relaxometric studies revealed that T-1 relaxivity of [Gd(DOTA-FP beta Gu)] changes in response to the concentration of beta-glucuronidase. Consistent with the relaxometric studies, [Gd(DOTA-FP beta Gu)] showed significant change in MR image signal in the presence of beta-glucuronidase and HSA. In vitro and in vivo MR images demonstrated appreciable differences in signal enhancement in the cell lines and tumor xenografts in accordance to their expression levels of beta-glucuronidase.[GRAPHICS].

  DOI：

  10.1021/ic301827p
• 作为产物：
  描述：

  D-glucurono-6,3-lactone 在 溴化钛(IV) 、 silver(l) oxide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 24.0h， 生成 1-O-(2-甲酰基-4-硝基苯基)-2,3,4-三-O-乙酰基-β-D-吡喃葡萄糖醛酸甲酯
  参考文献：
  名称：

  An Activity-Based Near-Infrared Glucuronide Trapping Probe for Imaging β-Glucuronidase Expression in Deep Tissues

  摘要：

  beta-glucuronidase is an attractive reporter and prodrug-converting enzyme. The development of near-IR (NIR) probes for imaging of beta-glucuronidase activity would be ideal to allow estimation of reporter expression and for personalized glucuronide prodrug cancer therapy in preclinical studies. However, NIR glucuronide probes are not yet available. In this work, we developed two fluorescent probes for detection of beta-glucuronidase activity, one for the NIR range (containing IR-820 dye) and the other for the visible range [containing fluorescein isothiocyanate (FITC)], by utilizing a difluoromethylphenol-glucuronide moiety (TrapG) to trap the fluorochromes in the vicinity of the active enzyme. beta-glucuronidase-mediated hydrolysis of the glucuronyl bond of TrapG generates a highly reactive alkylating group that facilitates the attachment of the fluorochrome to nucleophilic moieties located near beta-glucuronidase-expressing sites. FITC-TrapG was selectively trapped on purified beta-glucuronidase or beta-glucuronidase-expressing CT26 cells (CT26/m beta G) but not on bovine serum albumin or non-beta-glucuronidase-expressing CT26 cells used as controls. beta-glucuronidase-activated FITC-TrapG did not interfere with beta-glucuronidase activity and could label bystander proteins near beta-glucuronidase. Both FITC-TrapG and NIR-TrapG specifically imaged subcutaneous CT26/m beta G tumors, but only NIR-TrapG could image CT26/m beta G tumors transplanted deep in the liver. Thus NIR-TrapG may provide a valuable tool for visualizing beta-glucuronidase activity in vivo.

  DOI：

  10.1021/ja209335z

文献信息

• ANTIBODY-DRUG CONJUGATES
  申请人：CHO Pharma Inc.

  公开号：US20180133340A1

  公开（公告）日：2018-05-17

  An antibody-drug conjugate (ADC) has a structure represented by Formula (I): [D 2 -L 2 -Cn 2  y G 2 -Ab-Sg 1 G 1 -L 1 -D 1 ] x Formula (I) or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody without glycans (i.e., the protein portion of an antibody); G 1 and G 2 are glycan moieties, which may be the same or different; Cn 1 and Cn 2 are conjugation moieties, which may be the same or different; L 1 and L 2 are linker moieties, which may be the same or different; D 1 and D 2 are drug units which may be the same or different; and x and y are independently an integer from 0 to 8, provided that x+y≠0.

  一种抗体药物偶联物（ADC）具有以下式（I）所代表的结构： [D2-L2-Cn2yG2-Ab-Sg1G1-L1-D1]x 式（I） 或其药用可接受的盐，其中 Ab是没有糖基的抗体（即抗体的蛋白质部分）； G1和G2是糖基部分，可以相同也可以不同； Cn1和Cn2是结合基部分，可以相同也可以不同； L1和L2是连接基部分，可以相同也可以不同； D1和D2是药物单元，可以相同也可以不同； x和y分别是从0到8的整数，但要求x+y≠0。
• GLUCURONIDE PRODRUGS OF JANUS KINASE INHIBITORS
  申请人：THERAVANCE BIOPHARMA R&D IP, LLC

  公开号：US20180339990A1

  公开（公告）日：2018-11-29

  The invention relates to glucuronide prodrug compounds of Janus kinase (JAK) inhibitors having formula I: where W 1 , R 1 and A 1 are as defined. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to treat gastrointestinal inflammatory diseases; and processes and intermediates for preparing such compounds.

  本发明涉及具有公式I的糖苷酸前药化合物的Janus激酶（JAK）抑制剂：其中W1、R1和A1如所定义。本发明还涉及包含这些化合物的药物组合物；使用这些化合物治疗胃肠炎性疾病的方法；以及制备这些化合物的过程和中间体。
• [EN] GLUCURONIDE PRODRUGS OF TOFACITINIB<br/>[FR] PROMÉDICAMENTS À BASE DE GLUCURONIDE DE TOFACITINIB
  申请人：THERAVANCE BIOPHARMA R&D IP LLC

  公开号：WO2018165250A1

  公开（公告）日：2018-09-13

  The invention relates to glucuronide prodrug compounds of the Janus kinase (JAK) inhibitor tofacitinib having formula (I): (Formula (I)) where A1 and R1 are as defined. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to treat gastrointestinal inflammatory diseases; and processes and intermediates for preparing such compounds.

  这项发明涉及具有式(I)的Janus激酶（JAK）抑制剂托法替尼的葡萄糖醛酸酯前药化合物：（式(I)）其中A1和R1如所定义。该发明还涉及包含这种化合物的药物组合物；使用这种化合物治疗胃肠道炎症性疾病的方法；以及制备这种化合物的过程和中间体。
• Prodrugs of Anthracyclines for Use in Antibody-Directed Enzyme Prodrug Therapy
  作者：Jean-Claude Florent、Xia Dong、Gilbert Gaudel、Sofia Mitaku、Claude Monneret、Jean-Pierre Gesson、Jean-Claude Jacquesy、Martine Mondon、Brigitte Renoux、Solo Andrianomenjanahary、Sylvie Michel、Michel Koch、François Tillequin、Manfred Gerken、Joerg Czech、Rainer Straub、Klaus Bosslet

  DOI：10.1021/jm970589l

  日期：1998.9.1

  A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by

  报道了柔红霉素和阿霉素的一系列新前药，它们是抗体指导的酶前药治疗（ADEPT）的候选药物。这些化合物（25a，b，c和32a，b，c）经设计可在被β-葡萄糖醛酸苷酶激活后产生细胞毒性药物。如所期望的，在大肠杆菌β-葡糖醛酸糖苷酶以及从人β-葡糖醛酸糖苷酶和人源化CEA特异性结合区获得的融合蛋白进行酶促切割后，观察到活性药物的回收。这六种前药对鼠L1210细胞系的稳定性高，比阿霉素的细胞毒性低100倍以上。邻位取代的氨基甲酸苯酯25a，b，c比相应的对位取代的类似物更好地是β-葡萄糖醛酸苷酶的底物。
• [EN] EPOTHILONE ANALOGS FOR SITE SPECIFIC DELIVERY IN THE TREATMENT OF PROLIFERATIVE DISEASES<br/>[FR] ANALOGUES D'EPOTHILONE PERMETTANT L'ADMINISTRATION SPECIFIQUE D'UN SITE DANS LE TRAITEMENT DE MALADIES PROLIFERATIVES
  申请人：SCHERING AG

  公开号：WO2004050089A1

  公开（公告）日：2004-06-17

  Conjugates of epothilones and epothilone derivatives (as effectors) with suitable saccharides or saccharide derivatives (as recognition units) are described. Their production is carried out by the recognition units being reacted with suitable linkers, and the compounds that are produced are conjugated to the effectors. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.

  本文描述了用适当的糖或糖衍生物（作为识别单元）与紫杉醇类和紫杉醇衍生物（作为效应物）的共轭体。它们的生产是通过将识别单元与适当的连接剂反应，然后将产生的化合物与效应物共轭。本文还描述了共轭体在治疗增殖或血管生成相关过程中的药物用途。