N-Carboxyalkyl derivatives of 3-hydroxy-4-pyridinones: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation.
A set of three N-carboxyalkyl 3-hydroxy-4-pyridinones has been studied as bidentate M(III) chelators (M=Fe, Al, Ga), with potential for oral administration. After preparation of the ligands, their protonation constants (log K(i)) and the stability constants of their metal complexes have been determined. The distribution coefficients of these compounds, between 1-octanol and Tris buffer pH 7.4, were measured. The effect of these compounds on the biodistribution of 67Ga-citrate loaded rats was investigated and compared with that of the administered 67Ga-complexes. Results indicated that, among these chelating agents, the N-carboxyethyl derivative has the highest affinity towards this set of metal ions, irrespective of the metal, and that it could even compete with transferrin, the main Fe-plasma protein. The binding affinity and the hydrophilic character decrease with the increase in the size of the alkylic chain. The biological assays indicate that the complex formation in vivo is characterized by a high kinetics and thermodynamic stability, suggesting a competition with the transferrin. All the ligands were found to enhance the excretion of the gallium. Noteworthy is the observed Ga bone fixation, mostly with the ethyl derivative, thus suggesting the potential use of the complex as a bone seeking agent.
Santos
M Amélia
MA
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, Lisbon, Portugal. msantos@popsrv.ist.utl.pt
Gil
Marco
M
Marques
Sérgio
S
Gano
Lurdes
L
Cantinho
Guilhermina
G
Chaves
Sílvia
S
D000535:Aluminum / Q000378:metabolism*; D000818:Animals; D015913:Chelation Therapy; D005260:Female; D005708:Gallium / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D051379:Mice; D009942:Organometallic Compounds / Q000378:metabolism; D011522:Protons; D011728:Pyridones / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D013816:Thermodynamics; D017186:Titrimetry
D008024:Ligands; D009942:Organometallic Compounds; D011522:Protons; D011728:Pyridones; D005708:Gallium; D000535:Aluminum; D007501:Iron