Complexos de In(III) com ligantes polidentados derivados de bases de Schiff: propriedades físico-químicas e avaliação de seu potencial quimioterapêutico, radioquimioterapêutico e radiossensibilizador frente a células de tumores mamários

Abstract

In the present work complexes [In(2,6AcPh)Cl(H2O)] (1), [In(2,6AcpClPh)Cl(H2O)] (2) and [In(2,6AcpCH3Ph)Cl(H2O)] (3) with 2,6-diacetylpyridina-bis(benzoylhydrazone) (H2-2,6AcPh) and its bis(para-chloro-benzoylhydrazone) (H2-2,6AcpClPh) and bis(para-toluyl-hydrazone) (H2-2,6AcpCH3Ph) were obtained, as well as complexes [In(2,6FoPh)Cl(H2O)] (4), [In(2,6FopClPh)Cl(H2O)]·3H2O (5) and [In(2,6FopCH3Ph)Cl(H2O)]·H2O (6) with 2,6-difomylpyridine-bis(benzoylhydrazone) (H2-2,6FoPh) and its bis(para-chloro-benzoylhydrazone) (H2-2,6FopClPh) and bis(para-toluyl-benzoyllhydrazone) (H2-2,6FopCH3Ph) derivatives, and complexes [In(2,6AcSc)Cl(H2O)] (7) and [In(2,6AcTsc)Cl(H2O)] (8) with 2,6-diacetylpyridine-bis(semicarbazone) (H2-2,6AcSc) and 2,6- diacetylpyridine-bis(thiosemicarbazone) (H2-2,6AcTsc). In complexes (1 - 8) a dianionic ligand is attached to the metal center through the O-N-Npy-N-O chelating system in the bis(benzoylhydrazones) and bis(semicarbazone) and through the S-N-Npy-N-S chelating system in the bis(thiosemicarbazone). The crystal structures of (1) and (2) reveal a pentagonal bipyramidal arrangement, in which the In(III) center is bonded to a pentadentate ligand together with a chloride ion and a coordination water molecule. The increased conjugation and rigidity of the ligands in the complexes gives rise to fluorescence of (1-6) in DMSO in the 425-575 nm range. The quantum yields were lower than 1.5% taking quinine hemisulphate as standard. The compounds exhibited significant luminosities due to absorption in the near UV. Samples of the InCl3 precursor and of complexes (4), (6), (7) and (8) were submitted to neutron activation aiming to obtain the 114mIn analogs *InCl3, (*4), (*6), (*7) and (*8). The cytotoxic effects of the compounds were evaluated against MCF-7 (estrogen-dependent mammary adenocarcinoma), MDA-MB-231 (triple negative mammary adenocarcinoma), and MRC-5 (non-malignant human lung fibroblast) cells. The indium(III) complexes showed cytotoxic activity against breast tumor cells and an additive effect was observed by the combined treatment of the cells with the complexes and ionization radiation (chemotherapy with the In(III) complexes and radiotherapy with a 60Co source). Complex (4) and its analog (*4) exhibited higher cytotoxic activity than cisplatin against MCF-7 breast tumor cells at micromolar concentrations with feeble effects on MRC-5 non-malignant cells. The combined therapy using complex (4) at 1 μmolL-1 and radiation from a 60Co source and 1 Gy resulted in an increased percentage of cell death in the MDA-MB-231 > MCF-7 > MRC-5 order. Hence, complex (4) could act as a potential radiosensitizer, by increasing the therapeutic efficacy of radiation. Complexes (6) and (7) did not show cytotoxic activity against the three studied cell lineages whereas their radioactive analogs (*6) and (*7) were active at micromolar concentrations against MCF-7 cells. However, (*6), (*7) and cisplatin proved to be equally active against MRC-5 healthy cells. The combined therapy using radiation from a 60Co source and complexes (6) or (7) resulted in increased efficacy against the tumor as well as against the non-malignant cells, suggesting that the compounds are not able to act as potential radiosensitizers. Complex (8) at micromolar concentrations showed cytotoxic effects only against MCF-7 cells while its radioactive (*8) was active against both tumor cell lineages with therapeutic indexes TI1 = 7.7 (IC50 MRC-5 / IC50 MCF-7) e TI2 = 1.4 (IC50 MRC-5 / IC50 MDA-MB-231). Radiochemotherapy with (*8) resulted in an 11.14-fold decrease in IC50 against MCF-7 cells compared to the chemotherapy treatment with (8). Hence, complex (*8) could have potential applications in the radiochemotherapy of MCF-7 and MDA-MB-231 breast tumor cells. Complexes (4) and (6) were able to function as DNA intercalating agents while (8) did not show intercalating capacity. The present work constitutes an important contribution to the study of compounds with antineoplastic activity and to the development of therapeutic strategies to treat estrogen-positive and triple-negative breast tumors.