Thermodynamic Stability and Physicochemical Characterization of Ligand (4S)-4-Benzyl-3,6,10-tris(carboxymethyl)-3,6,10-triazadodecanedioic Acid (H5[(S)-4-Bz-ttda]) and Its Complexes Formed with Lanthanides, Calcium(II), Zinc(II), and Copper(II) Ions

Abstract

A derivative of H5ttda (=3,6,10-tris(carboxymethyl)-3,6,10-triazadodecanedioic acid=N-{2-[bis(carboxymethyl)amino]ethyl}-N-{3-[bis(carboxymethyl)amino]propyl}glycine), H5[(S)-4-Bz-ttda] (=(4S)-4-benzyl-3,6,10-tris(carboxymethyl)-3,6,10-triazadodecanedioic acid=N-{(2S)-2-[bis(carboxymethyl)amino]-3-phenylpropyl}-N-{3-[bis(carboxymethyl)amino]propyl}glycine; 1) carrying a benzyl group was synthesized and characterized. The stability constants of the complexes formed with Ca2+, Zn2+, Cu2+, and Gd3+ were determined by potentiometric methods at 25.0±0.1° and 0.1M ionic strength in Me4NNO3. The observed water proton relaxivity value of [Gd{(S)-4-Bz-ttda}]2− was constant with respect to pH changes over the range pH 4.5–12.0. From the 17O-NMR chemical shift of H2O induced by [Dy{(S)-4-Bz-ttda}]2− at pH 6.80, the presence of 0.9 inner-sphere water molecules was deduced. The water proton spin-lattice relaxation rate for [Gd{(S)-4-Bz-ttda}]2− at 37.0±0.1° and 20 MHz was 4.90±0.05 mM−1 s−1. The EPR transverse electronic relaxation rate and 17O-NMR transverse-relaxation time for the exchange lifetime of the coordinated H2O molecule (τM), and 2H-NMR longitudinal-relaxation rate of the deuterated diamagnetic lanthanum complex for the rotational correlation time (τR) were thoroughly investigated, and the results were compared with those previously reported for the other lanthanide(III) complexes. The exchange lifetime (τM) for [Gd{(S)-4-Bz-ttda}]2− (2.3±1.3 ns) was significantly shorter than that of the [Gd(dtpa)(H2O)]2− complex (dtpa=diethylenetriaminepentaacetic acid). The rotational correlation time τR for [Gd{(S)-4-Bz-ttda}]2− (70±6 ps) was slightly longer than that of the [Gd(dtpa)(H2O)]2− complex. The marked increase of relaxivity of [Gd{(S)-4-Bz-ttda}]2− mainly resulted from its longer rotational time rather than from its fast water-exchange rate. The noncovalent interaction between human serum albumin (HSA) and the [Gd{(S)-4-Bz-ttda}]2− complex containing the hydrophobic substituent was investigated by measuring the solvent proton relaxation rate of the aqueous solutions. The association constant (KA) was less than 100 M−1, indicating a weaker interaction of [Gd{(S)-4-Bz-ttda}]2− with HSA.