Síntese, citotoxicidade e estudo da relação estrutura-atividade de novas lactonas sesquiterpênicas derivadas da α-santonina

• Autor(a) principal: Arantes, Francisco Frederico Pelinson
• Data de Publicação: 2010
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: LOCUS Repositório Institucional da UFV
• Texto Completo: http://locus.ufv.br/handle/123456789/211
• topic: α-santonina; Herbicida; Lactonas sesquiterpênicas; α-Santonin; Herbicide; Sesquiterpene lactones; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA

Considering the wide spectrum of biological activities presented by sesquiterpene lactones, the few studies about the correlation structure-biological activity, as well as the limited availability of these compounds in nature, this work aims the synthesis, cytotoxicity and the study of structure-activity relationship of new sesquiterpene lactones derived from α-Santonin. The investigations resulted in the development of 21 compounds, with yields ranging from 4.5 to 100%. These compounds were prepared using different types of reactions (photochemical reactions, such as photooxygenation and photoaddition and oxidation reactions). The photochemical reactions were performed under various conditions, varying the solvent, the radiation source and type of reactor. The cytotoxicity of the compounds was tested against tumor cell lines: HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate) human cancer cell lines. The 6 compounds, which show the α-methylene-γ-butyrolactone group in their structure, exhibited relatively high cytotoxicity against tumor cell lines tested, with IC50 values in the range from 0.36 to 16.40 μmol L-1. Addition of an endoperoxide group to the compound 11,13-dehydromazdasantonin, giving a mixture of isomers, significantly increased the potency against tumor cell lines tested with IC50 values of 1.45 μmol L-1 (HL- 60), 2.54 μmol L-1 (SF-295), 4.35 μmol L-1 (HCT-8) and 3.26 μmol L-1 (MDA-MB-435). These results indicate that the endoperoxide group and the group α-methylene-y-butyrolactone have important roles in the mechanism by which the sesquiterpene lactones exert their cytotoxic activity. In order to deepen our understanding of structure-activity relationship of sesquiterpene lactones, was performed a quantum and chemometric study of sesquiterpene lactones with cytotoxic activity against tumor cells. The semi-empirical PM6 method was used to calculate a set of molecular descriptors of 20 sesquiterpene lactones with cytotoxic activity against tumor cells (HL-60). The Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were used to obtain possible relationships between the calculated descriptors and cytotoxicity of lactones. Four descriptors were identified as responsible for the separation between active and inactive compounds: EHOMO (highest occupied molecular orbital energy); Q11 (Net atomic charge on C11); Q12 (Net atomic charge on C12) and Q13 (Net atomic charge on C13). These results emphasized the importance of the group α-methylene-γ-butyrolactone to the cytotoxicity of sesquiterpene lactones.