Solution Structures, Stabilities, Kinetics, and Dynamics of DO3A and DO3A–Sulphonamide Complexes

Abstract

The Gd(3+)-DO3A-arylsulphonamide (DO3A-SA) complex is a promising pH-sensitive MRI agent. The stability constants of the DO3A-SA and DO3A complexes formed with Mg(2+), Ca(2+), Mn(2+), Zn(2+), and Cu(2+) ions are similar, whereas the logKLnL values of Ln(DO3A-SA) complexes are 2 orders of magnitude higher than those of the Ln(DO3A) complexes. The protonation constant (log KMHL) of the sulphonamide nitrogen in the Mg(2+), Ca(2+), Mn(2+), Zn(2+), and Cu(2+) complexes is very similar to that of the free ligand, whereas the logKLnHL values of the Ln(DO3A-SA) complexes are lower by about 4 logK units, indicating a strong interaction between the Ln(3+) ions and the sulphonamide N atom. The Ln(HDO3A-SA) complexes are formed via triprotonated *Ln(H3DO3A-SA) intermediates which rearrange to the final complex in an OH(-)-assisted deprotonation process. The transmetalation reaction of Gd(HDO3A-SA) with Cu(2+) is very slow (t1/2 = 5.6 × 10(3) h at pH = 7.4), and it mainly occurs through proton-assisted dissociation of the complex. The (1)H and (13)C NMR spectra of the La-, Eu-, Y-, and Lu(DO3A-SA) complexes have been assigned using 2D correlation spectroscopy (COSY, EXSY, HSQC). Two sets of signals are observed for Eu-, Y-, and Lu(DO3A-SA), showing two coordination isomers in solution, that is, square antiprismatic (SAP) and twisted square antiprismatic (TSAP) geometries with ratios of 86-14, 93-7, and 94-6%, respectively. Line shape analysis of the (13)C NMR spectra of La-, Y- , and Lu(DO3A-SA) gives higher rates and lower activation entropy values compared to Ln(DOTA) for the arm rotation, which indicates that the Ln(DO3A-SA) complexes are less rigid due to the larger flexibility of the ethylene group in the sulphonamide pendant arm. The fast isomerization and the lower activation parameters of Ln(DO3A-SA) have been confirmed by theoretical calculations in vacuo and by using the polarizable continuum model. The solid state X-ray structure of Cu(H2DO3A-SA) shows distorted octahedral coordination. The coordination sites of Cu(2+) are occupied by two ring N- and two carboxylate O-atoms in equatorial position. The other two ring N-atoms complete the coordination sphere in axial positions. The solid state structure also indicates that a carboxylate O atom and the sulphonamide nitrogen are protonated and noncoordinated.

A Bisamide Derivative of [Mn(1,4‐DO2A)] – Solution Thermodynamic, Kinetic, and NMR Relaxometric Studies

“…The final product was obtained in ca. 20 % yield after semipreparative HPLC-MS purification and was characterized by ESI-MS spectrometry and 1 H and 13 C NMR spectroscopy.…”

“…[12] [b] Ref. [13] shift changes over well-defined pH ranges, which are associated with the various protonation steps of the ligand. As the protonation/deprotonation processes are fast on the NMR time scale, the chemical shifts of the observed signals represent weighted averages of the shifts of the different species involved in a specific protonation step, see Equation (2).…”

“…[13] [b] Ref. [12] Notably, the metal complexes of 1,4-DO2AM show significantly lower stabilities compared with those of the corresponding complexes with 1,4-DO2A and 1,7-DO2A (Δlog K ML = 2.5-3.0).…”

Nyíltláncú és makrociklusos aminokarboxilát ligandumok szintézise és fémkomplexeik vizsgálata: koordinációs kémia az orvosi képalkotás szolgálatában

“…32 Vizsgálataink alapján a szulfonamid-oldalláncot tartalmazó DO3A származék ligandumok (DO3A-SA) Gd(III)-komplexei is alkalmasak erre. 31 Tanulmányoztuk a DO3A-SA ligandum és számos fémionnal képzett komplexének egyensúlyi, szerkezeti viszonyait, képzodési és disszociációs reakcióik kinetikai, valamint [Ln(DO3A-SA)]-komplexek dinamikai sajátosságait.…”

“…Disszociációs kinetikai vizsgálataink alapján a [Gd(DO3A-SA)]-komplex elegendoen inert a biológiai vizsgálatokhoz. 31 Egy másik példánk az "okos" kontrasztanyagokra a nitroimidazol (azomicin) "egységet" tartalmazó [Gd(DO3A-NIM)]-komplex. A ligandum szerkezetébol adódóan a Gd 3+ -komplex termodinamikailag stabil, kinetikailag inert, amely képes hipoxiás sejtekben dúsulni (a nitroimidazol "egység" nitrocsoportja reduktív közegben aminocsoporttá redukálódik, amely képes kovalens kötés kialakítására a sejten belül található különbözo makromolekulákkal, ez pedig gátolja a komplex "kiürülését").…”