5-benzyl-6-carboxymethyl-3-(([1-(N,N-dicarboxymethyl)-2'-aminomethyl]-cyclobut-1'-yl)methyl)-3,6-diazaoctanedionic acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 5-benzyl-6-carboxymethyl-3-(([1-(N,N-dicarboxymethyl)-2'-aminomethyl]-cyclobut-1'-yl)methyl)-3,6-diazaoctanedionic acid
• 英文别名: 2-[[1-[[Bis(carboxymethyl)amino]methyl]cyclobutyl]methyl-[2-[bis(carboxymethyl)amino]-3-phenylpropyl]amino]acetic acid
• 化学式: C₂₅H₃₅N₃O₁₀
• 分子量: 537.567
• InChiKey: FCISNXMIFGVVKI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.4
• 重原子数：
  38
• 可旋转键数：
  19
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  196
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  5-benzyl-6-carboxymethyl-3-(([1-(N,N-dicarboxymethyl)-2'-aminomethyl]-cyclobut-1'-yl)methyl)-3,6-diazaoctanedionic acid 、 水 、 氯化钆 在 NaOH 作用下， 以 水 为溶剂， 生成 [Gd(5-benzyl-6-carboxymethyl-3-(([1-(N,N-dicarboxymethyl)-2'-aminomethyl]-cyclobut-1'-yl)methyl)-3,6-diazaoctanedionic acid(-5H))(H2O)](2-)
  参考文献：
  名称：

  Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H₂O)]²⁻ Derivatives

  摘要：

  The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) both display high stability constant (log K-GdL = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K-(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K-(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K-(Gd/Zn) = 2.93), EPTPA-bz-NO2 (log K-(Gd/Zn) = 3.19), and DTPA (log K-(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature O-17 NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H2O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-). They are higher than those of [Gd(TTDA)(H2O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H2O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H2O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H2O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K-A) for [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K-A value for [Gd(Bz-CB-TTDA)(H2O)](2-) is lower than that of MS-325 (K-A = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H2O)](2-), [Gd(Bz-CB-TTDA)(H2O)](2-), and [Gd(DTPA)(H2O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H2O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H2O)](2-) make it a favorable blood pool contrast agent for MRI.

  DOI：

  10.1021/ic101799c

文献信息

• Ligand and metal complex
  申请人：Wang Yun-Ming

  公开号：US20110065905A1

  公开（公告）日：2011-03-17

  A ligand of Formula (I) is provided: wherein A 4 represents a hydrogen atom, a nitro group, an amino group, a thiocyanato group, or —Z—Y, in which Z is a divalent linking group and Y is a group derived from a biocompatible molecule, with the proviso that when X is methylene, A 4 cannot be a hydrogen atom or a nitro group. A metal complex having the ligand is also provided and is useful as a blood pool contrast agent or a targeting contrast agent.

  提供了一种Formula (I)的配体： 其中A4代表氢原子、硝基、氨基、硫氰基或—Z—Y，其中Z是二价连接基团，Y是源自生物相容分子的基团，但当X为亚甲基时，A4不能是氢原子或硝基。还提供了具有该配体的金属配合物，可用作血池造影剂或靶向造影剂。
• US8354512B2
  申请人：——

  公开号：US8354512B2

  公开（公告）日：2013-01-15
• Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H₂O)]²⁻ Derivatives
  作者：Ya-Hui Chang、Chiao-Yun Chen、Gyan Singh、Hsing-Yin Chen、Gin-Chung Liu、Yih-Gang Goan、Silvio Aime、Yun-Ming Wang

  DOI：10.1021/ic101799c

  日期：2011.2.21

  The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) both display high stability constant (log K-GdL = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K-(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K-(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K-(Gd/Zn) = 2.93), EPTPA-bz-NO2 (log K-(Gd/Zn) = 3.19), and DTPA (log K-(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature O-17 NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H2O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-). They are higher than those of [Gd(TTDA)(H2O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H2O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H2O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H2O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K-A) for [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K-A value for [Gd(Bz-CB-TTDA)(H2O)](2-) is lower than that of MS-325 (K-A = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H2O)](2-), [Gd(Bz-CB-TTDA)(H2O)](2-), and [Gd(DTPA)(H2O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H2O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H2O)](2-) make it a favorable blood pool contrast agent for MRI.