Browsing by Author "Zarate Méndez, Ana María"

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    Formation and characterization of crosslinks, including Tyr-Trp species, on one electron oxidation of free Tyr and Trp residues by carbonate radical anion
    (2020) Figueroa Alegría, Juan David; Zarate Méndez, Ana María; Fuentes Lemus, Eduardo Felipe; Davies, M. J.; Lopez Alarcon Camilo Ignacio
    Dityrosine and ditryptophan bonds have been implied in protein crosslinking. This is associated with oxidative stress conditions including those involved in neurodegenerative pathologies and age-related processes. Formation of dityrosine and ditryptophan derives from radical-radical reactions involving Tyr(center dot) and Trp(center dot) radicals. However, cross reactions of Tyr(center dot) and Trp(center dot) leading to Tyr-Trp crosslinks and their biological consequences have been less explored. In the present work we hypothesized that exposure of free Tyr and Trp to a high concentration of carbonate anion radicals (CO3 center dot-), under anaerobic conditions, would result in the formation of Tyr-Trp species, as well as dityrosine and ditryptophan crosslinks. Here we report a simple experimental procedure, employing CO3 center dot- generated photochemically by illumination of a Co(iii) complex at 254 nm, that produces micromolar concentrations of Tyr-Trp crosslinks. Analysis by mass spectrometry of solutions containing only the individual amino acids, and the Co(iii) complex, provided evidence for the formation ofo,o '-dityrosine and isodityrosine from Tyr, and three ditryptophan dimers from Trp. When mixtures of Tyr and Trp were illuminated in an identical manner, Tyr-Trp crosslinks were detected together with dityrosine and ditryptophan dimers. These results indicate that there is a balance between the formation of these three classes of crosslinks, which is dependent on the Tyr and Trp concentrations. The methods reported here allow the generation of significant yields of isolated Tyr-Trp adducts and their characterization. This technology should facilitate the detection, and examination of the biological consequences of Tyr-Trp crosslink formation in complex systems in future investigations.
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    Synthesis, antitumoral activity, and in silico studies on Smoothened receptor of new 2,6,9-trisubstituted purine derivatives
    (Elsevier B.V., 2025) Espinosa Bustos, Christian Marcelo; Zarate Méndez, Ana María; Castro Álvarez, Alejandro; Guerrero, Simón; Kogan, Marcelo J.; Salas Sánchez, Cristian Osvaldo
    © 2024 Elsevier B.V.In this work, a series of 30 new 2,6,9-trisubstituted purine derivatives were synthesised and evaluated in silico as potential ligands of the Smoothened (SMO) receptor, as well as their ability to inhibit growth in Hedgehog (Hh)-dependent and Hh-independent cancer cell lines. The synthesis involved a convergent strategy, conventional methods and microwave irradiation. Initial antitumour evaluation was performed by testing cell growth inhibition in seven cancer cell lines and one non-neoplastic cell line (HEK-293) at 50 μM. IC50 values were determined for compounds showing < 50 % cell viability. Compounds 7l and 9j showed promising results with high cytotoxicity in three Hh-dependent cell lines and low cytotoxicity in HEK-293 cells. Compound 7l was more potent and selective than gemcitabine in BxPC-3, AsPc-1 and MIA-PaCa-2 cells and more than 5-fluorouracil in HT-29 cells, while 9j was more potent and selective than 5-fluorouracil in HCT116 and HT-29 cells. Molecular docking studies in SMO allowed the recognition of two binding sites related to ligand size and purine substitution patterns, while 7l bound to the top pocket (TMD-1), 9j bound to a deeper pocket (TMD-2). This study provides new evidence supporting the purine ring as a privileged scaffold for the development of new antitumour drugs targeting the SMO receptor.