Alkylaryl-amino derivatives of 3-hydroxy-4-pyridinones as aluminium chelating agents with potential clinical application.
The neurotoxicity of aluminium is well established and so strategies for suitable aluminium chelating therapies, aimed at the treatment and/or amelioration of some neurological disorders, are of current interest. The present work describes a set of new bifunctional compounds containing a 3-hydroxy-4-pyridinone (3,4-HP) unit, as the aluminium chelating moiety, which is extra-functionalised with different alkyl-arylamine molecular segments, to account for the improvement on the biodistribution specificity of the chelating agents or the corresponding complexes. Besides the synthetic scheme, studies are performed to assess the properties of these compounds, namely in terms of lipophilicity, Al-chelating ability, speciation and in vivo 67Ga biodistribution. These studies show that the extrafunctional groups fortunately have small effects on the high Al chelating affinity of the 3,4-HP units, over a wide range of pH, but they lead to favourable changes on the lipo-hydrophilic balance of the ligands and on the complex speciation. Differences found in the biodistribution, namely the decrease of the blood-clearance rate and increase of the bone retention or the hepatobiliary excretion, seem to be mostly rationalized in terms of the increasing lipophilic character of the ligands.
D000535:Aluminum / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002951:Citrates / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D005708:Gallium / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D005710:Gallium Radioisotopes; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D000442:Octanols / Q000378:metabolism; D011522:Protons; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D014018:Tissue Distribution; D017186:Titrimetry
D002614:Chelating Agents; D002951:Citrates; D005710:Gallium Radioisotopes; D008024:Ligands; D000442:Octanols; D011522:Protons; D011728:Pyridones; D005708:Gallium; D000535:Aluminum