Impact of Metal Coordination on Cytotoxicity of 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone (Triapine) and Novel Insights into Terminal Dimethylation

The first metal complexes of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
(Triapine) were synthesized. Triapine was prepared by a novel three-step
procedure in 64% overall yield. In addition, a series of related ligands,
namely, 2-formylpyridine thiosemicarbazone, 2-acetylpyridine thiosemicarbazone,
2-pyridineformamide thiosemicarbazone, and their N4-dimethylated
derivatives (including the N4-dimethylated analogue of
Triapine) were prepared, along with their corresponding gallium(III)
and iron(III) complexes with the general formula [M(L)2]+, where HL is the respective thiosemicarbazone. The
compounds were characterized by elemental analysis, 1H
and 13C NMR, IR and UV−vis spectroscopies, mass
spectrometry, and cyclic voltammetry. In addition, Triapine and its
iron(III) and gallium(III) complexes were studied by X-ray crystallography.
All ligands and complexes were tested for their in vitro antiproliferative
activity in two human cancer cell lines (41M and SK-BR-3), and structure−activity
relationships were established. In general, the coordination to gallium(III)
increased the cytotoxicity while the iron(III) complexes show reduced
cytotoxic activity compared to the metal-free thiosemicarbazones.
Selected compounds were investigated for the capacity of inhibiting
ribonucleotide reductase by incorporation of 3H-cytidine
into DNA.