New Tris(hydroxypyridinones) as Iron and Aluminium Sequestering Agents: Synthesis, Complexation and In Vivo Studies

Abstract

Two new tripodal tris(3-hydroxy-4-pyridinone) hexadentate chelators-NTA(BuHP)(3) and NTP(PrHP)(3) (NTA=nitrilotriacetic acid, NTP=nitrilotripropionic acid, HP=hydroxypyridone)-have been developed and studied in solution for their iron and aluminium binding affinity, and also assayed in vivo for their capacity to remove metal from an animal model that is overloaded. These chelators are positional isomers, possessing identical general structures based on aminotricarboxylic acid skeletons attached to three bidentate 3-hydroxy-4-pyridinones (3,4-HPs), but differing in the position of the amide linkage along the chelating "arm". In spite of expected differences in the tripodal ligands, such as acidity and hydrogen-bonding networks, they share important properties, namely, a mild hydrophilic character (log P ca. -1.2 to -1.4) and a strong chelating affinity for Fe and Al (pFe=27.9 and pAl=22.0 for NTA(BuHP)(3); pFe=29.4 and pAl=22.4 for NTP(PrHP)(3)). They also evidenced identical effects on the biodistribution and on the excretion of a radiotracer ((67)Ga) previously administered to mice, as models of iron overload animals. Comparison of the new compounds with reported analogues shows good improvement in terms of solution and in vivo sequestering properties, thus giving support to expectations about their potential clinical application as metal removal agents.

A gallium complex with a new tripodal tris-hydroxypyridinone for potential nuclear diagnostic imaging: solution and in vivo studies of 67Ga-labeled species

“…Furthermore, a higher thermodynamic stability can be also expected for the NTP-than for the KEMPgallium complexes based on comparison with the corresponding iron complexes. In fact the corresponding pFe values differed on ca 1-order of magnitude [18], and identical behaviour can be expected for gallium systems due to the similarity of the ionic radius of these threecharged metal ions (Fe, 65 pm; Ga, 62 pm). It is also clearly shown that, for the micromolar conditions that prevail in biological systems, the tris-chelator NTP(PrHP) 3 presents a much higher metal chelating efficacy than the monohydroxypyridinone derivative, DFP, due to its higher denticity.…”

“…The stepwise protonation constants are depicted in Table 1, which also includes the corresponding values for other tripodal compounds and deferiprone (DFP), aimed at comparative purposes. NTP(PrHP) 3 has seven dissociable protons (H 7 L 4+ ), and the protonation constants (log K i ) depicted in Table 1 are assigned as follows: the first three values correspond to the three hydroxyl groups of the HP moieties; the fourth value is due to the backbone apical ammonium group; the last three values are attributable to the pyridinium protons of HP moieties [18]. This Table also includes the octanol/water partition coefficients (log P) for this ligand and other HP compounds at the physiological pH.…”

“…Since the galliumcomplex formation started below pH 2, the study of the Ga(III)/NTP (PrHP) 3 system required a spectrophotometric titration instead of a potentiometric technique. Thus, although the acid-base behaviour of the compound has already been studied by potentiometry [18], the spectral parameters for the different protonated species of the ligand were necessary for inclusion in the complexation model, and so a ligand spectrophotometric titration was also carried out.…”

“…Even though the most common PET radiolabelled compound is 18 F-FDG (18-fluorodeoxyglucose), it is reported to be of limited value for differentiation between various infectious and inflammatory conditions, and also it can only detect malignant cells with increased glucose metabolism [5,6]. Although 67 Ga-citrate has been mostly used in γ-scintigraphy, its limitations, namely due to nuclide binding to the plasma protein transferrin (resulting in relatively high background and therefore reduced lesion-to-background contrast), makes it less than ideal as an imaging agent.…”

“…Following our ongoing interest on searching for new strong polydentate HP for metal decorporation [15][16][17], we have recently developed a new series of very strong tripodal hexadentate-HP ironchelators (see Scheme 1) [18]. Since these ligands can provide full hexadentate coordination for Ga(III), we decided to investigate one of those new tripodal HP (Scheme 1; NTP(PrHP) 3 , p=2, n = 1) for the Ga(III) complexation properties in aqueous solution as well as the in vivo behaviour.…”