Síntese e Avaliação In Vitro da Atividade Antiglioma, Antioxidante e Inibidora da Monoaminoxidase-B de 2-imino-tiazolidin-4-onas

Abstract

A series of novel 2-imino-4-thiazolidinone (5a-p) derivatives was synthesized and evaluated for their cytotoxic activity against glioma (C6) cancer cell line, on the other hand, this work evaluated the antioxidant and neuroprotective actions of a synthetic molecule containing a 2-imino-4-thiazolidinone nucleus, the compound 3-(pyridin-2-yl)-2-(pyridine-2- ylimino)thiazolidin-4-one (PPIT). Among sixteen synthesized compounds (5a-p), three displayed potent antitumor activity against tested glioma cell line showed IC50 values well below the standard drug temozolomide (TMZ). Therefore, compounds 5a, 5l and 5p were evaluated cell cycle and death analysis, due potent toxicity (2.17±1.17, 6.24±0.59, 2.93±1.12, respectively) in C6 cell line. The mechanism of action studies demonstrated that 5a and 5l induced apoptosis significantly once increase the percentage of cells in Sub-G1 phase with absence of necrosis. Consistent with these results, caspase-3/7 assay revealed that 5l present pro-apoptotic activity due to the significant stimulation of caspases-3/7. Moreover, 5a, 5l and 5p increased antioxidant defense and decrease reactive oxygen species (ROS) production. According to compound 7, five in vitro assays were carried out in order to verify the antioxidant capacity of the compound: protein carbonylation (PC), ABTS, DPPH, FRAP and superoxide dismutase (SOD)-like activity. The results showed that PPIT reduced the brain levels of PC. Although no SOD mimetic activity was observed, the compound acted as a free radical scavenger (ABTS and DPPH) and exhibited reducing activity in the FRAP assay. In addition, the effects of PPIT on the activity of brain MAO isoforms (MAO-A and B) were investigated in vitro. Our data pointed to an inhibition of the MAO-B isoform by PPIT with no effect on MAO-A activity. Lastly, an acute oral toxicity test was conducted. No changes in food intake, body weight, and biochemical markers of kidney and liver damage were detected in mice treated with a high dose of PPIT. In conclusion, the present study demonstrated that compounds 5a, 5l, 5p and PPIT exhibits in vitro antiglioma activity and selectively inhibits the MAO-B isoform, respectively, without causing apparent toxicity.