Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators

Abstract

Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.

Design of iron chelators with therapeutic application

“…Unlike hexadentate and bidentate molecules, it is not possible to synthesise simple tridentate ligands which only possess oxygen anion coordination sites, 62 the central ligand typically being nitrogen. This has the adverse effect of rendering the iron(III) complex more easily reduced and therefore more susceptible towards redox cycling.…”

A Novel Tris(2-aminoethyl)amine Based Tripodal Ligand: Synthesis and Solution Coordination Studies with Trivalent Iron and Chromium

“…Much effort has been channeled into the synthesis of catechols [12] and hydroxamates [13][14][15][16] with typical examples (model chelators) being enterobactin and desferrioxamine, respectively. The most important work was carried out by the Raymond group who have reported numerous catecholate [17] and hydroxypyridone ligands [18,19]. A number of synthetic analogues have been prepared which retain the high affinity for iron(III) and with other metal ions, typical of enterobactin, and yet are more stable under biological conditions, for instance, the tripodal molecular Mecam [20].…”

Klinik Olarak Faydalı Demir Bağlayıcı Ligandların Tasarım Özellikleri

“…Buna karşılık, iki dişli ve üçlü dişli ligandlar, daha düşük moleküler ağırlıkları için oral olarak aktif olabildikleri için, altı dişli şelatörler açısından tercih edilebilir. Oral etkinlik bir ilacın yüksek talep edilen bir özelliğidir: tedavi maliyetlerini düşürür ve hastalar tarafından tolere edilebilirliği arttırır 8,10,12,13,14,15 .…”