Derivados p-Mentânicos : estudos de relação estrutura-atividade e avaliação de novos candidatos a agentes antitumorais

• Ano de defesa: 2015
• Autor(a) principal: Andrade, Luciana Nalone
• Orientador(a): Sousa, Damião Pergentino de
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Programa de Pós-Graduação: Pós-Graduação em Biotecnologia (RENORBIO-SE)
• Palavras-chave em Português: Biotecnologia; Câncer; Citotoxicidade; Agentes antineoplásicos; P-mentânicos; Atividade antitumoral
• Palavras-chave em Inglês: P-menthane monoterpenes; Cytotoxicity; Antitumor activity
• Área do conhecimento CNPq: OUTROS
• Link de acesso: http://ri.ufs.br/jspui/handle/riufs/12226

Cancer is a disease of high incidence, high mortality and difficult to treat, and there is therefore a constant social interest in the search for more effective therapies. In this sense, essential oils and their constituents are promising source of natural products as antitumor substances. Thus, the aim of this study was to evaluate the cytotoxic activity of 19 p-menthane derivatives structurally correlated with perillyl alcohol against three strains of human tumor cells: ovarian adenocarcinoma (OVCAR-8), colon carcinoma (HCT-116) and glioblastoma (SF-295) using the colorimetric MTT assay. The tests were performed in triplicate in a single concentration of 25 μg/ml. The results demonstrated that all substances tested were less cytotoxic than the perillyl alcohol, with the exception of 1,2-perillaldehyde epoxide (EP-1) and 8,9-periallaldehyde epoxide (EP-2) (IG = 95.66 to 99.89%) and IC50 ranging from 2.68 to 3.92 and 1.03 to 1.75 mg/ml, respectively. The perillyl benzoate was the least cytotoxic substance, with a value (GI = 2.86 to 5.02%). The monoterpenes (+)-limonene epoxide, (-)-hydroxy-carvone (-HC) and perillaldehyde had intermediate cytotoxic activity, with (IG = 58.40 to 94.01%). Given these results, the structural characteristics that can contribute to understand the cytotoxicity of perillyl alcohol and its analogs were identified. In general, substitution of C-C double bonds per epoxide groups added to the aldehyde group increased cytotoxicity. The presence and location of ketone and epoxide groups in p-menthane skeleton influence the cytotoxic activity. The addition of hydroxyl groups in the chemical structure resulted in less cytotoxic compounds, as was the case of the cis-carveol and sobrerol. As well, acetylation of such groups led to an overall decrease in cytotoxicity, indicating that lipophilicity plays a major role in the decrease of cytotoxic activity. In addition, the enantioselectivity to perform an important role in the cytotoxicity of natural compounds, as observed for (-)- and (+)-hydroxy-carvone. These results demonstrate that different functional groups and their positions in p-menthane skeleton influence the cytotoxic activity. Next was evaluated the in vivo antitumor activity of the compounds EP-1, EP-2 and (-HC) in Sarcoma 180-bearing mice (S180). In this test, the administration of EP-1 and EP-2 (100 or 200 mg/kg/day) inhibited the development in S180-inoculated mice. The inhibition was 33.4 and 56.4% for EP-1 and 38.4 and 58.7% for EP-2 at both doses, respectively. Already (-HC) (50 or 100 mg/kg/day) showed no antitumor activity in vivo. There were no changes in biochemical parameters in animals treated with EP-1 and EP-2. In relation to hematological analysis, these compounds showed a reduction in the number of total leukocytes and alterations in the differential count, a result expected as due to S180 tumor. The mechanism of action of EP-1 and EP-2 were then studied. None of the compounds tested induced hemolysis. The viability of HL-60 cells was affected by both monoterpenes after an exposure period of 24h, when analyzed by trypan blue exclusion. Both EP-1 and EP-2 reduced the number of viable cells associated with an increase in the number of non-viable cells, which contributes to the increased number of dead cells in the morphological analysis. The incorporation of ethidium bromide/acridine orange, the treated cells, cytotoxicity suggests apoptosis and necrosis pathway. Therefore, front of results, can conclude that EP-2 was more potent in vitro compared to EP-1, however, both substances showed cytotoxic activity through apoptotic and necrotic processes. These data suggest that EP-1 and EP-2 present a potential and promising anticancer potential and moreover, appropriate structural modifications are possible to develop novel anticancer agents.