Derivado hidantoínico 3,5-difenil-imidazolidina - 2,4 - diona com potencial antitumoral, antinociceptivo e antiedematogênico

• Ano de defesa: 2016
• Autor(a) principal: Beltrão, Daiene Martins
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos; UFPB
• Palavras-chave em Português: Hidantoína; Atividade antiangiogênica; Carcinoma ascítico de Ehrlich; Imunomodulação; Atividade antinociceptiva; Toxicidade; Hydantoin; Antiangiogenic activity; Ehrlich ascites carcinoma; Immunomodulation; Antinociceptive activity; Toxicity; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/15339

Cancer designate a group of heterogeneous genetic diseases characterized by uncontrolled cell proliferation. Problems in regard to effectiveness, safety as well as development of resistance to treatment foment the need for researches on new molecules with antitumor potential. Hydantoin derivatives are known to present biological activities such as antitumor and antinociceptive ones. This paper aimed at investigating the toxicity, antitumor, antinociceptive and antiinflammatory activities of the hydantoin derivative 3,5-diphenyl-imidazolidine - 2,4 – dione (IM-15). IM-15 did not induce hemolysis to the concentration of 2000 µg/mL, which suggested low toxicity in erythrocytes. In the pre-clinical acute toxicity trial, the IM-15 (300 or 2000 mg/kg, i.p.) induced a depressant effect on the Central Nervous System (CNS) and its LD50 (lethal dose 50%) was estimated at around 1000 mg/kg. The hydantoin derivative (12,5; 25 and 50 mg/kg, i.p.) reduced (p<0,001) all parameters (tumor volume and mass, and cell feasibility) in Ehrlich's ascitic carcinoma model, which characterizes its antitumor potential. It was observed that IM-15 did not interfere in the distribution of cells during the cell cycle. However, data showed that IM-15 reduced the peritumor vascular microvessel (p<0,05), cytokine levels IL4, TNFα, IFN-y, and chemokine CCl-2 (p<0,001). This suggests that the antitumor potential of such imidazolidine derivative involves the immune response modulation in connection to the control of cell proliferation, apoptosis and angiogenesis. Furthermore, the results suggest the angiogenesis reduction that was observed post-treatment with IM-15 is associated with the reduction of CCL2, TNF-α and IL-4, cytokines known as proangiogenic. Toxicological analysis indicate that the nine day treatment with the hydantoin derivative did not induce alterations in the biochemical and hematological parameters upon this study. In respect of the micronucleus trial, IM-15 (50 mg/kg, i.p.) did not induce the increase of the amount of micronucleated erythrocytes, thus, indicating low genotoxicity. IM-15 (50 mg/kg, i.p.) revealed antinociceptive activity in the hot plate, abdominal contortion and formalin trials, in which the last one had a stronger effect on the second phase, suggesting action in the inflammatory pain. It was shown that the mechanism of action involves neither the opioid's nor the GABAergic's pathways. Although, it does involve nitric oxide participation in the first phase of the formalin trial. IM-15 induced an antiedematogenic effect, but it did not minimize the peritonitis induced by carrageenan. Therefore, it is possible to infer that the IM-15 shows low toxicity and antitumor, antinociceptive and antiedematogenic activity.