Publicação
On the mode of action of prospective ruthenium anticancer metallodrugs and their metabolic and plasma stability
| Resumo: | Cancer is the second leading cause of death worldwide and is estimated to account for nearly 10 million deaths in 2020. Despite significant progress in developing new therapeutic options for the treatment of cancer, the drugs in clinical use still present major problems, such as non-selectivity and resistance to therapy, which are responsible for serious side effects and treatments’ failure. Thus, the synthesis and development of new anticancer agents capable of overcoming these problems is crucial. In this study, nine compounds with the general formula [Ru(η5 -CpR’)(PPh3)(2,2’-bipyridine-4,4’- R)]+ were tested against two breast cancer cell lines with different degrees of aggressiveness (MCF7/hormone-dependent and MDA-MB-231/triple negative). In vitro studies, aiming at establishing structure-activity relationships, encompassed the assessment of the cytotoxicity and clonogenic ability (antimetastatic potential) of these compounds. All compounds were cytotoxic against these cells and inhibited the formation of colonies, thus evidencing their potential antimetastatic activity. RT150 (R’ = CHO, R = CH3), RT151 (R’ = CH2OH, R = CH3), PMC79 (R’ = H, R = CH2OH) and LCR134 (R’ = H, R = CH2Biotin) emerged as the most promising compounds and were therefore selected for further studies concerning their intracellular distribution (drug internalization) and cell death mechanism. All these compounds were mainly retained at the membrane of both breast cancer cell lines and induced cell death by apoptosis. Finally, the stability of the four selected compounds was assessed towards plasmatic and hepatic metabolizing enzymes and their metabolic profile was established in the presence of Phase I and Phase II cofactors using high resolution mass spectrometry. RT151 and PMC79 exhibited high stability both in plasma and human liver microsomes and therefore represent promising compounds for in vivo tests. Compound LCR134 may need a drug delivery system to protect it from degradation until it reaches its target. RT150 requires further toxicological studies. |
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| Autores principais: | Maximiano, Inês Casquilho |
| Assunto: | Agentes anticancerígenos Complexos de Ruténio(II) ciclopentadienilo Linhas celulares de cancro da mama Farmacocinética Metabolitos Teses de mestrado - 2022 |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Cancer is the second leading cause of death worldwide and is estimated to account for nearly 10 million deaths in 2020. Despite significant progress in developing new therapeutic options for the treatment of cancer, the drugs in clinical use still present major problems, such as non-selectivity and resistance to therapy, which are responsible for serious side effects and treatments’ failure. Thus, the synthesis and development of new anticancer agents capable of overcoming these problems is crucial. In this study, nine compounds with the general formula [Ru(η5 -CpR’)(PPh3)(2,2’-bipyridine-4,4’- R)]+ were tested against two breast cancer cell lines with different degrees of aggressiveness (MCF7/hormone-dependent and MDA-MB-231/triple negative). In vitro studies, aiming at establishing structure-activity relationships, encompassed the assessment of the cytotoxicity and clonogenic ability (antimetastatic potential) of these compounds. All compounds were cytotoxic against these cells and inhibited the formation of colonies, thus evidencing their potential antimetastatic activity. RT150 (R’ = CHO, R = CH3), RT151 (R’ = CH2OH, R = CH3), PMC79 (R’ = H, R = CH2OH) and LCR134 (R’ = H, R = CH2Biotin) emerged as the most promising compounds and were therefore selected for further studies concerning their intracellular distribution (drug internalization) and cell death mechanism. All these compounds were mainly retained at the membrane of both breast cancer cell lines and induced cell death by apoptosis. Finally, the stability of the four selected compounds was assessed towards plasmatic and hepatic metabolizing enzymes and their metabolic profile was established in the presence of Phase I and Phase II cofactors using high resolution mass spectrometry. RT151 and PMC79 exhibited high stability both in plasma and human liver microsomes and therefore represent promising compounds for in vivo tests. Compound LCR134 may need a drug delivery system to protect it from degradation until it reaches its target. RT150 requires further toxicological studies. |
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