Synthesis, analysis and cytotoxic evaluation of some hydroxypyridinone derivatives on HeLa and K562 cell lines

Abstract

A range of iron bidentae ligands containing the chelating moiety 3- hydroxypyridin-4-ones (HPOs) have been synthesized via a single or a three-step synthetic pathway. In the single-step reaction, maltol was directly reacted by suitable primary amine and in the second synthetic method; benzylated maltol was reacted with related amines to give 1-substuted-2-methyl-3-benzyloxypyridin-4-one derivatives. Finally, removal of the benzyl group under acidic conditions was performed by catalytic hydrogenation to yield the favored bidentate chelators as HCl salt. The partition coefficient of the free ligands and their iron (III) complexes between an aqueous phase buffered at pH 7.4 and 1-octanol were also determined. The cytotoxic effects of these iron chelators against HeLa and K562 cell lines were evaluated using MTT assay and the results showed that cytotoxicity was closely related to the lipophilicity of compounds so that the most lipophilic compound (4g) revealed the highest activity and compound 4e as a more hydrophilic agent (Kpart; 0.05) showed the lowest cytotoxic effect.

Keywords: 3-Hydroxypyridin-4-ones; Cytotoxicity; HeLa and K562 cells; Iron chelating agents; Lipophilicity.

Fig. 1

Structures of desferrioxamine (DFO), diethylenetriamine pentaacetic acid (DTPA) and 3-hydroxypyridin-4-ones (HPOs)

Fig. 2

Synthesis of substituted 1-alkyl-3-hydroxypyridin-4-ones via a single or three steps synthetic pathway.

Fig. 3

Cytotoxic effects of HPO compounds against Hela cell line following exposure of 3 different concentrations of each compound. Cell viability was assessed using MTT assay. Data are presented as mean ± SD of cell survival compared to negative control (Cell survival of 100%) P<0.05(significantly different from control)

Fig. 4

Cytotoxic effects of HPO compounds against K562 cell line following exposure of 3 different concentrations of each compound. Cell viability was assessed using MTT assay. Data are presented as mean ± SD of cell survival compared to negative control (Cell survival of 100%) P<0.05 (significantly different from control).

Fig. 5

A possible condensation product in the synthesis of bidentate pyridin-4-ones from reaction of unprotected maltol with primary amines under basic conditions.

Fig. 6

Formation of 1-alkyl-3- hydroxypyridin-4-ones from reaction of protected maltol with alkyl amines under basic conditions.

Fig. 7

Formation of 1-aryl-3- hydroxypyridin-4-ones from reaction of unprotected maltol with aryl amines under acidic conditions. In these conditions, alkyl amines are completely protonated and therefore the nitrogen atom of this moiety would not act as a nucleophile to attack the maltol.