Machuqueiro, Miguel Ângelo dos SantosPires, Inês Domingos da Silva2023-03-2320232022http://hdl.handle.net/10451/56774Tese de mestrado, Bioquímica e Biomedicina , 2023, Universidade de Lisboa, Faculdade de CiênciasTriple-negative breast cancer is an aggressive subtype of breast cancer, lacking hormonal and human epidermal growth factor receptors, that render current targeted therapies used for other subtypes ineffective. Thus, treatment options are currently limited to classical chemotherapy drugs, such as cisplatin, that have known devastating side effects, while lacking selectivity. The current work focuses on the study of ruthenium-based compounds, that have shown promising anti-tumor capabilities, with increased selectivity for the tumor microenvironment. We studied three derivatives of TM34, substituted with a pH-sensitive linker based on hydrazone, and a peptide targeting triple-negative breast cancer cells. Their active species are substituted with a hydrazide group in the cyclopentadienyl coligand, or an acetyl group in the cyclopentadienyl or bipyridine coligands. The main goal of this work is to evaluate the impact of said derivations on the compound’s biophysical properties when interacting with a membrane model. By performing unrestrained Molecular Dynamics simulations, we studied the preferential partitioning region and orientation of the TM34 derivatives into the membrane phase, identifying their respective preferred insertion depth (∼1.3 nm from the membrane center), and their preference towards having the triphenylphosphine group oriented along the membrane normal vector and facing the membrane interior. Additionally, we performed Umbrella Sampling simulations, which allowed us to study the insertion profile of the compounds across the membrane, as well as their permeability coefficients. Despite being cations, all compounds had a strong preference towards the membrane phase, with an energy minimum below the average phosphate group position of the lipids, and permeability coefficient values comparable to those of other drugs currently used. Overall, we concluded that the acetyl substitution in the cyclopentadienyl ligands has significantly less impact on the compound’s membrane partitioning than the substitution with a hydrazine group, which we show introduces a higher desolvation penalty upon insertion.engComplexos ruténioDinâmica molecularUmbrella SamplingFármacos antitumoraisDifusão MembranarTeses de mestrado - 2023master thesis203486986