Estudo químico das partes aéreas e de compostos derivados do látex de Euphorbia tirucalli L. com avaliação citotóxica em adenocarcinoma gástrico

• Ano de defesa: 2023
• Autor(a) principal: Souza, Larissa Silva de
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal do Espírito Santo; BR; Doutorado em Química; Centro de Ciências Exatas; UFES; Programa de Pós-Graduação em Química
• Palavras-chave em Português: Euphorbia tirucalli; Partes aéreas; Látex; Citotoxicidade; Triterpenos; Ésteres diterpênicos; subject.br-rjbn; Química
• Link de acesso: http://repositorio.ufes.br/handle/10/16721

Euphorbia tirucalli L. is a plant used in folk medicine for the treatment of various diseases, including cancer and, recently, also for gastric ulcers. Two popular preparations are used. One is prepared by adding six drops of latex to two liters of water and the other is an ethanolic extract produced from the aerial parts of the plant. The chemical composition of the latex comprises about 80.0% of a mixture of major triterpenoids and minor ingenol 3-monoesters and, for the aerial parts, triterpenes and phenolic compounds have been described. However, diterpene esters have been found to be co-carcinogenic and the use of plant parts has been associated with Burkitt's Lymphoma. Therefore, the objective of this study was to propose more selective products against gastric adenocarcinoma (AGS), derived from the latex of E. tirucalli, as well as to determine the cytotoxicity on AGS cells for the ethanolic extract of aerial parts. Extracts and products obtained had their chemical profiles determined by GC-MS, ESI(-) FT-ICR MS, 1H NMR and ESI(-)-LTQ-MS/MS. The products were obtained, either from latex, by preparative chromatography on a silica gel column (triterpene mixture and diterpene ester mixture), or from hydrolyzed latex, as triterpene esters, by structural modification of the major triterpenes. The aerial parts were collected to produce ethanolic extract, as well as its liquid/liquid partition products. Ingenol 3-monoesters were studied in silico due to their similarity with pharmaceutical application molecules and their affinity for the active site of protein kinase C delta (PKCδ) in the C1b domain, a pro-apoptotic protein. As a result, the ethanolic extract of aerial parts showed smaller selectivity for AGS cells when compared to latex (SI 4.58 and 7.52, respectively). Its hexanic (IC50 10.33 ± 2.01 µg/mL) and aqueous (IC50 13.08 ± 0.99 µg/mL) partitions, containing eufol/tirucalol and ellagic acid, respectively, in their compositions, were considered the most active. When produced from latex, the hydrolyzed products were highly cytotoxic, but their selectivity was decreased. Regarding the cytotoxicity of natural product classes, triterpenes (IC50 9.16 ± 0.26 µg/mL) and acetylated triterpenes (IC50 23.13 ± 1.1 µg/mL) were more cytotoxic than diterpene esters (IC50 65.19 ± 0.09 µg/mL), although the latter were more selective. In molecular anchorage, the ingenol 3-esters had high affinity to the PKCδ C1b domain, such as the molecule ingenol 3-angelato, constituent of Picato®, a drug indicated for actinic keratosis. The PKCδ protein is overexpressed in cancer cells and is related to their programmed cell death. In conclusion, greater cytotoxicity on AGS cells was found for triterpenes, although diterpene esters were more selective. Hydrolyzed latex, less selective than the original latex, but free of diterpene esters, is also a future prospect for gastric cancer. Finally, the greater cytotoxicity of the ethanolic extract of the aerial parts of E. tirucalli for AGS seems to result from the synergism between ellagic acid and triterpenes.