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Estudo da citotoxidade e mecanismo de acção de complexos binucleares de ferro e ouro em linhas tumorais
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Esta dissertação descreve o trabalho que teve como objectivo estudar a actividade citotóxica e contribuir para o conhecimento do mecanismo de acção de compostos conjugados de ferroceno com aminoácidos (triptofano, prolina e metionina) e complexos de ouro (N-Au-PPh3, N-Au-PPh2py, S-Au-PPh3, S-Au- (C6F5)3) em linhas tumorais. Fez-se uso de duas linhas tumorais humanas, HeLa (células endoteliais do cancro do colo do útero) e MCF-7 (células epiteliais do cancro da mama) e de uma linha tumoral não-humana, N1E-115 (células isoladas a partir do clone adrenérgico derivado de neuroblastoma C-1300 de murganho). No que diz respeito à citotoxicidade, seis dos nove compostos testados apresentaram valores de IC50 promissores, entre os 10 - 88 μM. Observaram-se diferenças de actividade anti-proliferativa para os diferentes tipos celulares. O conjugado de ferroceno mais eficaz está associado ao aminoácido metionina e ao complexo de Ouro, S-Au-PPh3. Foram levados a cabo estudos biológicos e de interacção dos compostos com a molécula de DNA, com o intuito de obter informações sobre o mecanismo de acção destes potenciais fármacos. Dos primeiros estudos concluiu-se que a apoptose é, provavelmente, um dos mecanismos de morte celular que decorre da actividade destes e que a produção de espécies reactivas de oxigénio poderá estar na sua origem. A interacção dos compostos com a molécula de DNA não parece ser por intercalação.
The work described in this thesis aimed at studying the cytotoxic activity and contribute to the knowledge of the mechanism of action of conjugates of ferrocene with aminoacids (tryptophan, proline and methionine) and gold complexes (N-Au- PPh3, N-Au-PPh2py, S-Au-PPh3, S-Au-(C6F5)3) in tumour cell lines. Three tumour cell lines were used, HeLa (derived from cervical cancer), MCF-7 (derived from breast cancer) and N1E-115 (derived from mouse sympathetic ganglion neurons of C-1300 mouse). Cytotoxicity studies with six out of nine of the tested compounds presented showed promising IC50 values, ranging from 10 to 88 μM. Differences of antiproliferative activity were observed for the different types of cell lines. The more efficient conjugate of ferrocene is associated with methione and to a golden complex, S-Au-PPh3. Biological assays and studies of interaction of compounds with DNA were carried out, aiming to increase knowledge about the mechanism of action of these potential drugs. It was concluded that apoptosis is, probably, one of the mechanisms that arises from the activity of these compounds. Production of reactive oxygen species may be at the origin of apoptosis. Intercalation does not seem to be the way the studied compounds interact with the DNA molecule.
The work described in this thesis aimed at studying the cytotoxic activity and contribute to the knowledge of the mechanism of action of conjugates of ferrocene with aminoacids (tryptophan, proline and methionine) and gold complexes (N-Au- PPh3, N-Au-PPh2py, S-Au-PPh3, S-Au-(C6F5)3) in tumour cell lines. Three tumour cell lines were used, HeLa (derived from cervical cancer), MCF-7 (derived from breast cancer) and N1E-115 (derived from mouse sympathetic ganglion neurons of C-1300 mouse). Cytotoxicity studies with six out of nine of the tested compounds presented showed promising IC50 values, ranging from 10 to 88 μM. Differences of antiproliferative activity were observed for the different types of cell lines. The more efficient conjugate of ferrocene is associated with methione and to a golden complex, S-Au-PPh3. Biological assays and studies of interaction of compounds with DNA were carried out, aiming to increase knowledge about the mechanism of action of these potential drugs. It was concluded that apoptosis is, probably, one of the mechanisms that arises from the activity of these compounds. Production of reactive oxygen species may be at the origin of apoptosis. Intercalation does not seem to be the way the studied compounds interact with the DNA molecule.
Descrição
Tese de mestrado, Bioquímica (Bioquímica Médica), Universidade de Lisboa, Faculdade de Ciências, 2009
Palavras-chave
Bioquímica Médica Teses de mestrado - 2009