Novel 3-hydroxy-2(1H)-pyridinones. Synthesis, iron(III)-chelating properties and biological activity

Abstract

The synthesis of a range of novel bidentate and hexadentate ligands containing the chelating moiety 3-hydroxy-2(1H)-pyridinone is described. The pKa values of the ligands and the stability constants of their iron(III) complexes have been determined. The stability constant of the iron(III) complex of one of the hexadentate ligands is comparable to that of desferrioxamine B. The distribution coefficients of the ligands and their iron(III) complexes were also determined. One of the novel hexadentate compounds has been shown to markedly enhance iron(III) excretion from both hepatocytes and iron-overloaded mice.

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…Hexadentate hydroxypyridinone analogs. In another attempt to reduce the production of redox active partial complexes and increase complex stability, various hexadentate hydroxypyridinone analogs have been synthesized and analyzed (Streater et al, 1990;Cohen et al, 2000;Xu et al, 2002). One hexadentate ligand known as TREN-(Me-3,2-HOPO) (Fig.…”

Design of Orally Active Iron Chelators

“…Thus, whereas only the 3-hydroxypyridin-4-ones are efficient at removing iron from iron-overloaded mammals in the bidentate form [13], hexadentate hydroxamates and 3-hydroxypyridin-2-ones are capable of scavenging iron under biological con ditions [14],…”

The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia

“…dropyridin-l-yl)acetamido]ethylamine was synthesized as previously described [18]. Desferrioxamine (DFX) was obtained from Ciba-Geigy Ltd. (Basle, Switzerland).…”

“…There is considerable interest in the development of synthetic orally active iron chelators to replace DFX clinically. A series of hydroxypyridones with various substitutions have been synthesised [18]. These are bidentate ligands and three molecules of the chelator are therefore required to chelate completely 1 ferric ion.…”