Synthesis and characterizations of pyridazine-based iron chelators

Abstract

In an attempt to design ligands which require both a high iron(III) affinity and a low iron(II) affinity, the 3-hydroxypyridin-4-one structure has been modified to introduce an additional nitrogen atom in the pyridine ring to form a pyridazine. The target molecules were synthesized from a chlorine-substituted pyridazine using step-by-step methoxylations. A total of six 3- and 5-hydroxypyridazin-4(1H)-ones have been synthesized, with a methyl, ethyl or n-propyl group on the N1 of the pyridazine ring. In the reaction of the pyridazines with alkyl iodide, the presence of acetone drives the reaction to afford pyridazinones rather than the desired pyridaziniums. The pK(a) values of the free ligands, the stability constants of their iron(III) complexes and corresponding pFe(III) values demonstrate that this type of ligand has lower values when compared with those of deferiprone. The reduction potential values of the iron complexes obtained from cyclic voltammetry measurements, are used to determine the corresponding pFe(II) values. Although two compounds of the 20 series have marginally higher log β3(Fe(III))/log β3(Fe(II)) ratios than those of deferiprone, they possess pFe(III) values <20, indicating that this type of chelator is unlikely to be optimized into a useful therapeutic agent.

Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones – Attempted optimization of the orally active iron chelator, deferiprone

“…values of 3-hydroxy-4(1H)-pyridone, together with the rate of metabolism, a range of monomethyl, dimethyl and trimethyl analogues of deferiprone (7)(8)(9)(10) have been investigated, the results of which are reported in this communication.…”

“…Thus the introduction of an additional nitrogen into the ring leading to the 3-hydroxypyridazin-4-one (2) and 5-hydroxypyridazin-4-one (3) groups has been investigated. [10] However the introduction of the additional nitrogen, leads to a marked reduction in the affinity for iron(III); the pFe 3+ values being 20.6, 14.8, 17.2 for 1, 2 and 3 respectively. [10] In order to successfully scavenge iron from iron overloaded tissues, a minimum pFe 3+ value of 20 is required.…”

“…[10] However the introduction of the additional nitrogen, leads to a marked reduction in the affinity for iron(III); the pFe 3+ values being 20.6, 14.8, 17.2 for 1, 2 and 3 respectively. [10] In order to successfully scavenge iron from iron overloaded tissues, a minimum pFe 3+ value of 20 is required. [5] The introduction of fluorine into the hydroxypyridinone structure has been investigated.…”

Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator

“…The 2 largest chelatable iron pools are, first, within hepatocytes where more than 70% of body iron is deposited and, second, iron released from macrophages after the catabolism of red cells 19. The most rapidly chelatable iron pool within cells is the so-called labile iron pool (LIP), which is relatively small at any moment and is predominantly contributed to by intracellular ferritin catabolism 19,20…”

Comparative solution studies and cytotoxicity of gallium(III) and iron(III) complexes of 3-hydroxy-2(1H)-pyridinones

“…In addition to the aqueous solution studies, the in vitro cytotoxicity of the Ga(III) complexes in multidrug resistant and doxorubicin-sensitive human colon adenocarcinoma cell lines was studied. As complexation of Ga(III) and Fe(III) has been widely characterized with other 3-hydroxy-2pyridinone and 3-hydroxy-4-pyridinone type ligands in solution [16,[19][20][21][22][23], stoichiometry and stability of EHP and EHMP complexes were compared to the analogous hydroxypyridinone complexes.…”