Bifunctional 3-hydroxy-4-pyridinone derivatives as potential pharmaceuticals: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation with 67Ga.
A series of extra-functionalized 3-hydroxy-4-pyridinone chelators of hard metal ions, containing different side-chains with peptidomimetic groups, was studied to assess the effect of those groups on the physico-chemical properties, the metal-chelating affinity and the in vivo behaviour of the compounds, in view of their potential pharmaceutical applications. Besides the synthesis of the chelators, the study of their properties in aqueous solution alone and in the presence of M (3+) (M = Fe, Ga and Al) was performed by potentiometric/spectroscopic techniques. The octanol/water partition coefficient values of these hydroxypyridinone derivatives cover ca. 3 orders of magnitude (1.1 > log P > -2). They all form very stable tris-chelated M(III) complexes, the pFe and pGa values ranging up to five orders of magnitude. The in vivo studies showed the effect of the ligands on the biodistribution of (67)Ga citrate and also of (67)Ga-complexes in mice, in view of the potential use of the ligands or complexes as metal decorporating or as imaging agents, respectively. Although almost all these peptidomimetic hydroxypyridinone derivatives present very rapid clearance rate from most organs, the L-ornithine derivative (H(2)L(9)) shows to be superior to the others and as good as Deferiprone as metal decontaminant of Ga. Concerning the (67)Ga complexes, the benzyl-propylamine (H(2)L(3)) shows considerable bone retention, thus suggesting its potential application as imaging agent.
Santos
M Amélia
MA
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, 1049-001 Lisboa, Portugal. masantos@ist.utl.pt
Gil
Marco
M
Gano
Lurdes
L
Chaves
Sílvia
S
D000535:Aluminum / Q000737:chemistry*; D000818:Animals; D000077543:Deferiprone; D015195:Drug Design; D005708:Gallium / Q000737:chemistry*; D005710:Gallium Radioisotopes; D007501:Iron / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D005710:Gallium Radioisotopes; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D000077543:Deferiprone; D005708:Gallium; D000535:Aluminum; D007501:Iron