Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas. Programa de Pós-Graduação em Química / Made available in DSpace on 2013-03-04T18:12:27Z (GMT). No. of bitstreams: 1 305437.pdf: 14714811 bytes, checksum: ca8844eea7bbeec9a2f40a9249243d80 (MD5) / Na busca por novas moléculas com potencial biológico, o objetivo deste trabalho foi complementar o estudo fitoquímico do extrato diclorometano de Wilbrandia ebracteata, bem como o isolamento dos constituintes majoritários deste e do extrato diclorometano de Luffa operculata para utilização como material de partida na obtenção de análogos de cucurbitacinas. Foram isoladas e caracterizadas 2 novas cucurbitacinas naturais e os compostos majoritários di-hidrocucurbitacina B, cucurbitacina R e cucurbitacina B foram obtidas em quantidades superiores a 15 g. Através de modificações estruturais aplicadas seguindo diferentes estratégias de modificação molecular, como variação de grupos substituintes, simplificação e extensão de cadeia, foram obtidos 55 derivados semissintéticos. As cucurbitacinas naturais e semissintéticas foram avaliadas quanto às propriedades anti-herpética, citotóxica frente a linhagens de células tumorais e antiinflamatória. Estudo de QSAR realizado com os compostos ativos frente à linhagem de células de carcinoma de pulmão (A549) sugeriram que a morte celular provocada pelas cucurbitacinas nas células tumorais pode estar associada a ataques eletrofílicos e a distribuição eletrônica no anel A. / Searching for molecules with biological potential, the aim of this work was to complement the phytochemical study of the dichloromethane extract of Wilbrandia ebracteata roots, as well as the isolation of its major constituents from it and the dichloromethane extract of Luffa operculata, in order to use them as starting material for the synthesis of cucurbitacins analogues. Two new natural cucurbitacins were isolated and characterized and the major compounds dihydrocucurbitacin B (CN-1), cucurbitacin R (CN-3) and cucurbitacin B (CN-7) were obtained in adequate quantities for use as starting material in the synthesis of derivatives. Through the applying of structural changes using different strategies of medicinal chemistry, such as variation of substituent groups, simplification and chain extention, 55 cucurbitacins derivatives were obtained. In the ring A, modifications of the a-hydroxy ketone group were made by nucleophilic substitution, esterification and deoxygenation of the hydroxyl at position 2; at the ring B, the formation of a,ß-unsaturated ketone was performed; the hydroxyl in position 16 at the ring D was oxidized, deoxygenated or converted to ester; the side chain was cleaved, the a,ß-unsaturated ketone was modified and the C-25 acetyl was eliminated. The natural and semisynthetic cucurbitacins were evaluated for their anti-herpetic, cytotoxicity against tumor cell lines and anti-inflammatory properties. In the anti-herpetic activity assays, only CS-46 analog showed some activity, but with low selectivity index. Against the tumor cell lines analyzed, A549, RD, KB, HCT-8 and RD, the best results were obtained with the natural cucurbitacins CN-3, CN-4, CN-5 and CN-7, with IC50 values between 0.01 and 7.22 ìM, and with cucurbitacin B derivatives CS-15 (2.64 ìM), CS-34 (0.12 ìM), CS-41 (0.12 ìM) and CS-44 (11.52 ìM), for A549 cell line. QSAR studies suggest that the cell death caused by cucurbitacins may be associated with electrophilic attacks and eletronic distribuition in ring A. With regard to anti-inflammatory activity, cucurbitacin B derivatives CS-34 and CS-44 showed promising activity, with IC50 = 0.66 and 1.04 ìM, respectively.