Síntese e atividade antiglioblastoma in vitro e in vivo de 2,4- tiazolidinedionas

Abstract

Thiazolidinediones (TZDs) are an important class of heterocyclic compounds that have versatile biological activities, including anticancer action. In the present study, seventeen 2,4-thiazolidinediones were synthesized, identified, characterized and analyzed for anti-glioblastoma activity. The synthesis of the compounds was performed through Knoevenagel and N-alkylation reactions in a one-pot methodology using a microwave oven suitable for the laboratory in 40 minutes. The chemical structures were identified and characterized by gas chromatography coupled to mass spectrometer (GC-MS) and by nuclear magnetic resonance of hydrogen and carbon (1H and 13C NMR). The anti- glioma activity was evaluated in vitro by the MTT colorimetric assay and afterwards, an in vivo study was carried out by intracerebroventricular implantation of glioblastoma C6 cells in Wistar rats. The behavioral (object recognition and open field tasks) and serum biochemical parameters were determined in the preclinical model. All the synthesized compounds reduced cell viability in the C6 glioblastoma cell line and fifteen compounds were cytotoxic in the GL261 mouse line. None of the compounds showed toxicity in primary astrocyte culture, thus showing selectivity for tumor cells. The compounds 4CI IC50 = 28.51 μM and 4DI IC50 = 54.26 μM, both with R2 = 4-F, showed the best results, therefore, it was assumed that the fluorine atom in position four of ring B is important for anti-glioblastoma activity. Compound 4CI, with the lowest IC50, was selected for the in vivo analysis, in which it was found that the treatment for 15 days with the dose of 10 mg/kg administered by intragastric route was able to qualitatively reduce the tumor volume and normalize the glycemic levels. There was no change in the serum lipid profile and protein content, as well as no changes in the biochemical markers of renal damage. As regards liver damage markers, it was observed that aspartate aminotransferase levels were not altered in any of the experimental groups; however, an increase was detected in alanine aminotransferase caused by treatment. The 4CI compound reverted the hypolocomotion found in untreated animals, as well as the reduction in weight gain induced by glioblastoma. According to the results obtained in the in vitro tests, all compounds were promising for anti-glioblastoma activity, mainly 4CI, which obtained the greatest reduction in the viability of C6 cells and also low toxicity in astrocyte culture. 4CI also demonstrated anti-glioblastoma activity in vivo, thus being a potential candidate for preclinical studies in other animal models.