Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential.
The synthesis of a range of novel bidentate ligands containing the chelating moiety 3-hydroxy-4(1H)-pyridinone is described. The pKa values of the ligands and the stability constants of their iron(III) complexes have been determined. The crystal structures of one of the ligands and one of the iron(III) complexes are presented. The distribution coefficients of the ligands are reported and are related to the ability of the ligands to remove iron from hepatocytes. The influence of 3-hydroxy-4(1H)-pyridinones on oxidative damage to cells is described. In contrast to the iron chelator in current therapeutic use, desferrioxamine-B, many of the bidentate ligands described in this study are orally active in iron-overloaded mice.
Dobbin
P S
PS
Department of Pharmacy, King's College London, U.K.
Hider
R C
RC
Hall
A D
AD
Taylor
P D
PD
Sarpong
P
P
Porter
J B
JB
Xiao
G
G
van der Helm
D
D
D000284:Administration, Oral; D000818:Animals; D003461:Crystallography; D003676:Deferoxamine / Q000494:pharmacology; D006736:Horses; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007502:Iron Chelating Agents; D011728:Pyridones; D007501:Iron; D003676:Deferoxamine