TY - JOUR
T1 - Lanthanide Complexes of DO3A-(Dibenzylamino)methylphosphinate
T2 - Effect of Protonation of the Dibenzylamino Group on the Water-Exchange Rate and the Binding of Human Serum Albumin
AU - Urbanovský, Peter
AU - Kotek, Jan
AU - Carniato, Fabio
AU - Botta, Mauro
AU - Hermann, Petr
N1 - Publisher Copyright:
© Copyright 2019 American Chemical Society.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)-drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu 3 DO3A, formaldehyde, and Bn 2 NCH 2 PO 2 H 2 ethyl ester. The ligand protonation and metal ion (Gd 3+ , Cu 2+ , and Zn 2+ ) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (logK A = 5.8) was 1 order of magnitude lower than that of the free ligand (log K A = 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17 O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast ( M = 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (13% and 70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2-3 times increased at pH = 4-7. The relaxivity for the supramolecular HSA-complex adduct (r 1 b ) is as high as 52 mM -1 s -1 at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin-drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.
AB - Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)-drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu 3 DO3A, formaldehyde, and Bn 2 NCH 2 PO 2 H 2 ethyl ester. The ligand protonation and metal ion (Gd 3+ , Cu 2+ , and Zn 2+ ) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (logK A = 5.8) was 1 order of magnitude lower than that of the free ligand (log K A = 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17 O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast ( M = 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (13% and 70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2-3 times increased at pH = 4-7. The relaxivity for the supramolecular HSA-complex adduct (r 1 b ) is as high as 52 mM -1 s -1 at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin-drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.
UR - http://www.scopus.com/inward/record.url?scp=85064438849&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.9b00267
DO - 10.1021/acs.inorgchem.9b00267
M3 - Article
SN - 0020-1669
VL - 58
SP - 5196
EP - 5210
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 8
ER -