Synthesis and physicochemical characterization of two gadolinium(III) TTDA-like complexes and their interaction with human serum albumin.
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)](2-) (117 x 10(6) s(-1)) and [Gd(TTDA-N'-BOM)(H(2)O)](2-) (131 x 10(6) s(-1)) are significantly higher than those of [Gd(DTPA)(H(2)O)](2-) (4.1 x 10(6) s(-1)) and [Gd(BOPTA)(H(2)O)](2-) (3.45 x 10(6) s(-1)). The rotational correlation time (tau) values for [Gd(TTDA-BOM)(H(2)O)](2-) (119 ps) and [Gd(TTDA-N'-BOM)(H(2)O)](2-) (125 ps) are higher than those of [Gd(DTPA)(H(2)O)](2-) (103 ps) and [Gd(TTDA)(H(2)O)](2-) (104 ps). The stepwise stoichiometric binding constants of [Gd(TTDA-BOM)(H(2)O)](2)(-) and [Gd(TTDA-N'-BOM)(H(2)O)](2)(-) bound to HSA are obtained by ultrafiltration studies. Fluorescent probe displacement studies exhibit that [Gd(TTDA-BOM)(H(2)O)](2-) and [Gd(TTDA-N'-BOM)(H(2)O)](2-) 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)](2-) and [Gd(TTDA-N'-BOM)(H(2)O)](2-) 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)](2-)/HSA and [Gd(TTDA-N'-BOM)(H(2)O)](2-)/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)](2-)/HSA and [Gd(DTPA-BOM(3))(H(2)O)](2-)/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)](2-) complex which was added to the [Gd(TTDA-N'-BOM)(H(2)O)](2-)/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)].
Ou
Ming-Hung
MH
Faculty of Medicinal and Applied Chemistry, Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Republic of China.
Tu
Chien-Hung
CH
Tsai
Su-Ching
SC
Lee
Wei-Thung
WT
Liu
Gin-Chung
GC
Wang
Yun-Ming
YM
D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005682:Gadolinium / Q000737:chemistry*; D006801:Humans; D007850:Lauric Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D019216:Metals, Heavy / Q000737:chemistry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010103:Oxygen Isotopes; D012015:Reference Standards; D012680:Sensitivity and Specificity; D012709:Serum Albumin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013696:Temperature
C511699:3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid-benzyloxymethyl; D001593:Benzyl Compounds; D002614:Chelating Agents; D007850:Lauric Acids; D008024:Ligands; D019216:Metals, Heavy; D009942:Organometallic Compounds; D010103:Oxygen Isotopes; D012709:Serum Albumin; C496928:gadolinium 3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid; D005682:Gadolinium