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Cobalt(III) complexes are well-suited systems for cytotoxic drug release under hypoxic conditions. Here, we investigate the effect of cytotoxic azide release by cobalt-containing carrier-prototypes for antitumoral prodrugs. In addition, we study the species formed after reduction of Co(3+) → Co(2+) in the proposed models for these prodrugs. Three new complexes, [Co(III)(L)(N3)2]BF4(1), [{Co(II)(L)(N3)}2](ClO4)2(2), and [Co(II)(L)Cl]PF6(3), L=[(bis(1-methylimidazol-2-yl)methyl)(2-(pyridyl-2-yl)ethyl)amine], were synthesized and studied by several spectroscopic, spectrometric, electrochemical, and crystallographic methods. Reactivity and spectroscopic data reveal that complex 1 is able to release N3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH6.2, 7.0 and 7.4) and acetonitrile solutions. The antitumoral activities of compounds 1-3 were tested in normoxia on MCF-7 (human breast adenocarcinoma), PC-3 (human prostate) and A-549 (human lung adenocarcinoma epithelial) cell lines, after 24h of exposure. Either complexes or NaN3 presented IC50 values higher than 200 μM, showing lower cytotoxicity than the clinical standard antitumoral complex cisplatin, under the same conditions. Complexes 1-3 were also evaluated in hypoxia on A-549 and results indicate high IC50 data (>200 μM) after 24h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 μM. Regarding complex 3, no cytotoxic activity was observed in the same conditions. The data presented here indicate that the tridentate ligand L is able to stabilize both oxidation states of cobalt (+3 and +2). In addition, the cobalt(III) complex generates the low cytotoxic cobalt(II) species after reduction, which supports their use as as carrier prototypes for antitumoral prodrugs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Continuing our interest in tridentate ligands to develop new prototypes of cobalt-based metallodrugs for combating cancer, modifications in the backbone of HL1, [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]amine) were proposed in order to modulate the redox potential of new Co(III) complexes. Three ligands with electron withdrawing groups were synthesized: HL2: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]amine); HL3: [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]imine) and HL4: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]imine). They were used to obtain the respective mononuclear complexes 2, 3 and 4, which are discussed compared to the previous reported complex 1 (obtained from HL1). The new complexes were characterized and studied by several techniques including X-ray crystallography, elemental and conductimetric analysis, IR, UV-vis and (1)H NMR spectroscopies, and electrochemistry. The substitutions of the group in the para position of the phenol (HL1 and HL2) and the imine instead of the amine (HL3 and HL4), promote anodic shifts in the complexes reduction potentials. The influence of these substitutions in the biological activities of the Co(III) complexes against the murine melanoma cell line (B16F10) was also evaluated. Little effect was observed on cellular viability decrease for all free ligands, however the coordination to Co(III) enhances their activities in the following range: 1>4≈2>3. The data suggest that no straight correlation can be addressed between the reduction potential of the Co(III) center and the cell viability., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Cisplatin and its analogues are some of the most widely used anticancer drugs. However, toxicity and resistance have limited their use, and gallium compounds have emerged as an alternative, due to their remarkable antitumor activity and low toxicity. In this paper, we report on four new mononuclear gallium(III) complexes with the general formula [ Ga(bhi-R) 2 ] + , where bhi-R ( R = – NO 2 , – Br , – Cl and – OCH 3 ) is the deprotonated form of imidazole/phenol-containing tridentate Schiff bases. The molecular structures of C1 – C4 were solved by single crystal X-ray diffraction revealing mononuclear and isostructural complexes, with the metal center in distorted octahedral geometries. In all cases, the gallium(III) is coordinated to two ligand molecules arranged in meridional fashion, through the imidazole and imino nitrogen atoms, and to the phenolate oxygen. Complexes C1 – C4 were also characterized in solution by spectroscopic and spectrometric techniques. DFT calculations were performed to assist the interpretation of experimental results, and also allowed to establish the reasons why only meridional isomers were obtained. The stability of all complexes was evaluated in PBS buffer (1% DMSO) over 24 h, and results indicate partial hydrolysis in this period. Finally, the biological activity of C1 – C4 was evaluated on human tumor cell lines MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma epithelial) and PC-3 (prostate adenocarcinoma). Complex C1 was the most active, being effective and selective for A-549. The IC 50 (94.12 ± 4.62) of C1 is lower than the value (135.10 ± 6.50) obtained for cisplatin, which was tested as a metallodrug reference under the same experimental conditions. [ABSTRACT FROM AUTHOR]