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

Abstract

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 N(4)-dimethylated derivatives (including the N(4)-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, (1)H and (13)C 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 (3)H-cytidine into DNA.

Vanadium(IV/V) complexes of Triapine and related thiosemicarbazones: Synthesis, solution equilibrium and bioactivity

“…The enlongated bond length of V-O2 can be explained by the trans influence of the oxido ligand and is in agreement with a similar structure with 2-acetylpyridine-4-phenylthiosemicarbazone [35]. In crystal structures of both, 1a and 2a, deprotonation of the PTSC ligand is accompanied with a distinct elongation of the C7-S bond (1a: 1.737 Å; 2a: 1.751 Å) compared to the metal-free ligand at 1.686 Å indicating an increased single-bond character [7]. In addition, the C7-N3 bond decreases from 1.373 Å to 1.325 Å in 1a and 1.334 Å in 2a, respectively.…”

“…Therefore, we prepared only the vanadium complexes of the terminally dimethylated ligands (PTSC and APTSC) for further biological studies. The two metal-free ligands APTSC and PTSC were synthesized according to literature [7,31]. The V(V)O 2 -containing complexes were synthesized in methanol in 1:2 molar ratio using the appropriate TSC ligand (HL) and the vanadium(V) precursor Single crystals of X-ray diffraction quality of 1a were obtained after several days directly from the mother liquor.…”

“…The results of the X-ray diffraction studies are shown in Fig. 5 and selected bond distances and angles are summarized in Table 5 for 1a and 2a in comparison to the PTSC ligand [7]. For the vanadium(V) complex 1a ( Table 5 In contrast, in the oxovanadium(IV) complex 2a, the coordination polyhedron approaches an octahedron, where one tridentate PTSC, a bidentate acac, and an oxido ligand is coordinated to the metal center (Fig.…”

“…Cu(II), Zn(II), Ru(III), Pt(II), and Pd(II), which can result in complexes with even higher cytotoxicity than that of the metal-free ligands [2]. In our previous works we pointed out that dimethylation of the terminal nitrogen strongly enhances the cytotoxicity of α(N)-pyridyl TSCs, especially in the absence of any NH 2 group in the molecule [7]. In addition,…”

“…terminal dimethylation results in a strong increase of the solution stability of the Fe(II/III), Cu(II), Zn(II), and Ga(III) complexes [7][8][9]. The best-known terminally dimethylated bispyridyl TSC is di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which demonstrated very potent anticancer activity in vivo using human xenografts in nude mice [10,11] and was reported to overcome multidrug-resistance in cancer cells [12].…”