Gallium(III) and Iron(III) Complexes of α-N-Heterocyclic Thiosemicarbazones:  Synthesis, Characterization, Cytotoxicity, and Interaction with Ribonucleotide Reductase

Abstract

A series of gallium(III) and iron(III) complexes with five different 4N-substituted alpha-N-heterocyclic thiosemicarbazones, viz., 2-acetylpyridine N,N-dimethylthiosemicarbazone (1), 2-acetylpyridine N-pyrrolidinylthiosemicarbazone (2), acetylpyrazine N,N-dimethylthiosemicarbazone (3), acetylpyrazine N-pyrrolidinylthiosemicarbazone (4), and acetylpyrazine N-piperidinylthiosemicarbazone (5), with the general formula [GaLCl2] (HL = 1 and 2) and [ML2][Y] (M = Ga, HL = 1-5, Y = PF6; M = Fe, HL = 1-5, Y = FeCl4 and PF6) were synthesized and characterized by elemental analysis, a number of spectroscopic methods (NMR, IR, UV-vis), mass spectrometry, and X-ray crystallography. The in vitro antitumor potency was studied in two human cancer cell lines (41M and SK-BR-3). The central metal ions exert pronounced effects in a divergent manner: gallium(III) enhances, whereas iron(III) weakens the cytotoxicity of the ligands. The capacity of ligand 1 and its Ga(III) and Fe(III) complexes to destroy the tyrosyl radical of the presumed target ribonucleotide reductase is reported.

Ruthenium(II) Complexes of Thiosemicarbazones: The First Water‐Soluble Complex with pH‐Dependent Antiproliferative Activity

“…[19,20] Interest in ruthenium was stimulated by phase I clinical trials of two ruthenium complexes, namely (H 2 im)[trans-Ru III Cl 4 (Him)(dmso)] (NAMI-A; Him = imidazole) and (H 2 ind)[transRu III Cl 4 (Hind) 2 ] (KP1019; Hind = indazole), the first as an antimetastatic drug and the second as an anticancer agent against primary tumours and metastases, and in particular colon carcinomas. [21,22] The very high cytotoxicity of our recently synthesised gallium(III) and iron(III) complexes with N 4 -substituted α-N-heterocyclic thiosemicarbazones [23] in vitro together with the above-mentioned interest in ruthenium chemistry prompted us to synthesise novel ruthenium complexes of thiosemicarbazones. We chose two ligands, 2-acetylpyridine N 4 ,N 4 -dimethylthiosemicarbazone (HL 1 ), which shows very high cytotoxicity in the low nanomolar range and the ability to destroy the tyrosyl radical of mouse ribonucleotide reductase R2 protein, [23] and phenanthrenequinone thiosemicarbazone (HL 2 ), which is known to have antiproliferative activity in the low micromolar range.…”

“…[21,22] The very high cytotoxicity of our recently synthesised gallium(III) and iron(III) complexes with N 4 -substituted α-N-heterocyclic thiosemicarbazones [23] in vitro together with the above-mentioned interest in ruthenium chemistry prompted us to synthesise novel ruthenium complexes of thiosemicarbazones. We chose two ligands, 2-acetylpyridine N 4 ,N 4 -dimethylthiosemicarbazone (HL 1 ), which shows very high cytotoxicity in the low nanomolar range and the ability to destroy the tyrosyl radical of mouse ribonucleotide reductase R2 protein, [23] and phenanthrenequinone thiosemicarbazone (HL 2 ), which is known to have antiproliferative activity in the low micromolar range. [24] The presence of the phenanthrene moiety in HL 2 renders this ligand capable of DNA intercalation in addition to its potential ribonucleotide reductase inhibiting properties.…”

Copper thiosemicarbazones: Antiproliferative action against C6 glioma cells

“…The high cyto -toxic effect of 2 is probably due to the complex as an entity. Some reported cytotoxicity of metal complexes with acetylpyridine and acetylpyrazine-derived Nheterocyclic thiosemicarbazones against the 41 M (ovarian carcinoma), SK-BR-3 (mammary carcinoma) and SW480 (colon carcinoma) human cancer cell lines with IC50 values in the nanomolar range (Enari et al, 1998;Kowol et al, 2007). However, to the best of our knowledge the present work reports for the first time the cytotoxicity of copper complexes against brain tumor cells.…”

Crystal structure of 4-formylpyridine thiosemicarbazonium nitrate hydrate, [C7H9N4S][NO3] · H2O

“…Thiosemicarbazones and their deviatives have been the subject of extensive investigation primarily because of their biological activities, such as antitumor [1,2], antiviral [3], antibacterial [4], antimalarial [5], antifungal [6], anti-inflammatory [7] and anti-HIV activities [8] and remarkable coordination properties [9][10][11]. The title compound was obtained within our project of studying thiosemicarbazones coordination compounds as potential anti-HIV-1 drugs.…”