1-O-(2-difluoromethyl-4-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl))acetamido)phenyl)-β-D-glucopyranuronate | 1407150-80-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-O-(2-difluoromethyl-4-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl))acetamido)phenyl)-β-D-glucopyranuronate
• 英文别名: DOTA-FPβGu；(2S,3S,4S,5R,6S)-6-[2-(difluoromethyl)-4-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 1407150-80-4
• 化学式: C₂₉H₄₁F₂N₅O₁₄
• 分子量: 721.666
• InChiKey: FBHNUIYLXVWNPO-LGUFPPMKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -10.6
• 重原子数：
  50
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  270
• 氢给体数：
  8
• 氢受体数：
  20

反应信息

• 作为反应物：
  描述：

  europioum(III) chloride 、 1-O-(2-difluoromethyl-4-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl))acetamido)phenyl)-β-D-glucopyranuronate 、 水 在 sodium hydroxide 作用下， 反应 24.0h， 生成 [Eu(1-O-(2-difluoromethyl-4-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl))acetamido)phenyl)-β-D-glucopyranuronate)(H₂O)]
  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：

  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

文献信息

• Development of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for β-Glucuronidase Activity Profiling
  作者：Shih-Hsien Chen、Yu-Ting Kuo、Gyan Singh、Tian-Lu Cheng、Yu-Zheng Su、Tzu-Pin Wang、Yen-Yu Chiu、Jui-Jen Lai、Chih-Ching Chang、Twei-Shiun Jaw、Shey-Cherng Tzou、Gin-Chung Liu、Yun-Ming Wang

  DOI：10.1021/ic301827p

  日期：2012.11.19

  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].