两种类钆（III）TTDA配合物的合成、物理化学表征及其与人血清白蛋白的相互作用

Synthesis and physicochemical characterization of two gadolinium(III) TTDA-like complexes and their interaction with human serum albumin.

作者信息

Ou Ming-Hung, Tu Chien-Hung, Tsai Su-Ching, Lee Wei-Thung, Liu Gin-Chung, Wang Yun-Ming

机构信息

Faculty of Medicinal and Applied Chemistry, Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Republic of China.

出版信息

Inorg Chem. 2006 Jan 9;45(1):244-54. doi: 10.1021/ic050329r.

DOI:10.1021/ic050329r

PMID:16390062

Abstract

Two novel derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), TTDA-BOM and TTDA-N'-BOM, each having a benzyloxymethyl group, were synthesized. (17)O NMR longitudinal and transverse relaxation rates and chemical shifts of aqueous solutions of their Gd(III) complexes were measured at variable temperature with a magnetic field strength of 9.4 T. The water exchange rate (k(ex)(298)) values for Gd(TTDA-BOM)(H(2)O) (117 x 10(6) s(-1)) and Gd(TTDA-N'-BOM)(H(2)O) (131 x 10(6) s(-1)) are significantly higher than those of Gd(DTPA)(H(2)O) (4.1 x 10(6) s(-1)) and Gd(BOPTA)(H(2)O) (3.45 x 10(6) s(-1)). The rotational correlation time (tau) values for Gd(TTDA-BOM)(H(2)O) (119 ps) and Gd(TTDA-N'-BOM)(H(2)O) (125 ps) are higher than those of Gd(DTPA)(H(2)O) (103 ps) and Gd(TTDA)(H(2)O) (104 ps). The stepwise stoichiometric binding constants of Gd(TTDA-BOM)(H(2)O)(-) and Gd(TTDA-N'-BOM)(H(2)O)(-) bound to HSA are obtained by ultrafiltration studies. Fluorescent probe displacement studies exhibit that Gd(TTDA-BOM)(H(2)O) and Gd(TTDA-N'-BOM)(H(2)O) can displace dansylsarcosine from HSA with inhibition constants (K(i)) of 1900 and 1600 microM, respectively; however, they are not able to displace warfarin. These results indicate that Gd(TTDA-BOM)(H(2)O) and Gd(TTDA-N'-BOM)(H(2)O) have a weak binding to site II on HSA. In addition, the mean bound relaxivity (r(1b)) and bound relaxivity (r(1)(b)) values for the Gd(TTDA-BOM)(H(2)O)/HSA and Gd(TTDA-N'-BOM)(H(2)O)/HSA adducts are obtained by ultrafiltration and relaxivity studies, respectively. The bound relaxivity of these adducts values are significantly higher than those of Gd(BOPTA)(H(2)O)/HSA and Gd(DTPA-BOM(3))(H(2)O)/HSA. These results also suggest that bound relaxivity is site dependent. In binding sites studies of Gd(III) chelates to HSA, a significant decrease of the relaxation rates (R(1obs)) was observed for the Eu(TTDA-BOM)(H(2)O) complex which was added to the Gd(TTDA-N'-BOM)(H(2)O)/HSA solution, and this indicated that these Gd(III) complexes share the same HSA binding site. Finally, as measured by the Zn(II) transmetalation process, the kinetic stability of these Gd(III) complexes are significantly higher than that of [Gd(DTPA-BMA)(H(2)O)].

摘要

合成了两种新型的TTDA（3,6,10 - 三（羧甲基）- 3,6,10 - 三氮杂十二烷二酸）衍生物TTDA - BOM和TTDA - N'-BOM，它们各自含有一个苄氧基甲基。在9.4 T的磁场强度下，于可变温度下测量了它们的Gd(III)配合物水溶液的(17)O NMR纵向和横向弛豫率以及化学位移。[Gd(TTDA - BOM)(H₂O)]²⁻（117×10⁶ s⁻¹）和[Gd(TTDA - N'-BOM)(H₂O)]²⁻（131×10⁶ s⁻¹）的水交换率（k(ex)(298)）值显著高于[Gd(DTPA)(H₂O)]²⁻（4.1×10⁶ s⁻¹）和[Gd(BOPTA)(H₂O)]²⁻（3.45×10⁶ s⁻¹）。[Gd(TTDA - BOM)(H₂O)]²⁻（119 ps）和[Gd(TTDA - N'-BOM)(H₂O)]²⁻（125 ps）的旋转相关时间（tau）值高于[Gd(DTPA)(H₂O)]²⁻（103 ps）和[Gd(TTDA)(H₂O)]²⁻（104 ps）。通过超滤研究获得了[Gd(TTDA - BOM)(H₂O)]²⁻和[Gd(TTDA - N'-BOM)(H₂O)]²⁻与HSA结合的逐步化学计量结合常数。荧光探针置换研究表明，[Gd(TTDA - BOM)(H₂O)]²⁻和[Gd(TTDA - N'-BOM)(H₂O)]²⁻能够从HSA中置换丹磺酰肌氨酸，抑制常数（K(i)）分别为1900和1600 μM；然而，它们不能置换华法林。这些结果表明，[Gd(TTDA - BOM)(H₂O)]²⁻和[Gd(TTDA - N'-BOM)(H₂O)]²⁻与HSA上的位点II具有弱结合。此外，分别通过超滤和弛豫率研究获得了[Gd(TTDA - BOM)(H₂O)]²⁻/HSA和[Gd(TTDA - N'-BOM)(H₂O)]²⁻/HSA加合物的平均结合弛豫率（r(1b)）和结合弛豫率（r(1)(b)）值。这些加合物的结合弛豫率值显著高于[Gd(BOPTA)(H₂O)]²⁻/HSA和[Gd(DTPA - BOM(3))(H₂O)]²⁻/HSA。这些结果还表明结合弛豫率是位点依赖性的。在Gd(III)螯合物与HSA的结合位点研究中，对于添加到[Gd(TTDA - N'-BOM)(H₂O)]²⁻/HSA溶液中的[Eu(TTDA - BOM)(H₂O)]²⁻配合物，观察到弛豫率（R(1obs)）显著降低，这表明这些Gd(III)配合物共享相同的HSA结合位点。最后，通过Zn(II)转金属化过程测量，这些Gd(III)配合物的动力学稳定性显著高于[Gd(DTPA - BMA)(H₂O)]。