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Naphthoylhydrazones: coordination to metal ions and biological screening

Publication . Ribeiro, Nadia; Galvao, Adelino M.; Gomes, Clara S. B.; Ramos, Helena; Pinheiro, Rute; Saraiva, Lucilia; Ntungwe, Epole; Isca, Vera; Rijo, Patricia; Cavaco, Isabel; Ramilo-Gomes, Filipa; Guedes, Rita C.; Pessoa, Joao Costa; Correia, Isabel

We report the synthesis of 3-hydroxyl-2-naphthoylhydrazones containing pyrrole (HL1), furane (HL2) and thiophene (HL3) moieties and their V(IV)O-, Cu(II)- and Zn(II)-complexes. All compounds are characterized by the usual analytical techniques and coordination of the ligands to the metal ions is discussed based on spectroscopic data (FTIR, UV-vis, EPR and NMR) as well as CAMB3LYP DFT/TDDFT calculations, indicating the formation of neutral ML2 type complexes. The photophysical properties of ligands and complexes are disclosed. The binding to Bovine Serum Albumin (BSA) is evaluated in detail using several spectroscopic tools. Circular dichroism shows that the compounds, and particularly the ligand precursors, stabilize BSA, increasing its a-helical content. Fluorescence studies indicate the formation of 1 : 1 protein-compound adducts, which is corroborated by molecular docking studies that show the interaction between Trp 213 of BSA and the naphthalene rings. The general toxicity is evaluated using the Artemia salina lethality assay, with all compounds showing general toxicity towards the brine shrimp model. The cytotoxicity on human cancer cells (H1299, MCF7, and HCT116) is assessed for all compounds and the half-maximal inhibitory concentration (IC50) values are in the range from 0.57 to 27.35 mu M. Compounds containing L-1 (pyrrole derivative) are the most cytotoxic, with the vanadium and zinc complexes performing better than the copper ones, and some of them depicting IC50 values lower than 1.1 mM. However, selectivity needs improvement as the compounds show toxicity towards Artemia salina and normal fibroblasts.

2019-12Journal article

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New Cu(II) complexes with pyrazolyl derived schiff base ligands: synthesis and biological evaluation

Publication . Ribeiro, Nadia; Roy, Somnath; Butenko, Nataliya; Cavaco, Isabel; Pinheiro, Teresa; Alho, Irina; Marques, Fernanda; Avecilla, Fernando; Pessoa, Joao Costa; Correia, Isabel

Since the discovery of cisplatin there has been a continuous pursuit for new metallodrugs showing higher efficacies and lower side effects. In this work, new copper(II) complexes (C1-C6) of Schiff bases derived from pyrazolyl were developed. Through condensation of 5-methyl-1H-pyrazole-3-carbohydrazide with different aromatic aldehydes - pyridoxal, salicylaldehyde, 3-methoxy-2-hydroxybenzaldehyde, 3-ethoxy-2-hydroxybenzaldehyde and 2-hydroxynaphthene-l-carbaldehyde a set of new pyrazole based "ONO" tridentate Schiff bases were obtained in moderate to good yields - L1-L6, as well as their Cu(II)-complexes. All compounds were characterized by analytical techniques and their molecular formulae established. The antioxidant potential of all compounds was tested, yielding low activity in most cases, with the exception of L1 and C5. The Cu(II) complexes were tested for their aqueous stability, and for their interaction with biological molecules, namely DNA and HSA (human serum albumin), through fluorescence quenching experiments (and electrophoresis for DNA). With the exception of C3, all the synthesized complexes were able to interact with DNA and HSA. Their cytotoxic activity against two cancer cell lines (MCF7 - breast and PC3 - prostate) was also evaluated. Complexes C5 and C6, with larger aromatic systems, showed much higher cytotoxicity (in the low mu M range), than C1-C4, as well as IC50 values much lower than cisplatin. For C6 the results suggest that the mechanisms of cell death do not seem to be mediated by apoptosis, through caspases 3/7 activation, but by involving membrane potential and imbalance in physiological elements such as P, K and Ca.

2017-09Journal article

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Evaluation of the binding of four anti-tumor Casiopeinas to human serum albumin

Publication . Correia, Isabel; Borovic, Sladjana; Cavaco, Isabel; Matos, Cristina P.; Roy, Somnath; Santos, Hugo M.; Fernandes, Luz; Capelo, Jose L.; Ruiz-Azuara, Lena; Pessoa, Joao Costa

The metal complexes designated by Casiopeinas (R) are mixed-ligand Cu-II-compounds some of them having promising antineoplastic properties. We report studies of binding of Cu(glycinato)(4,7-dimethyl-1,10-phenanthroline) (Cas-II-Gly (1)), Cu(acetylacetonato)(4,7-dimethy1-1,10-phenanthroline) (Cas-III-Ea (2)), Cu(glycinato) (4,4'-dimethyl-2,2'-bipyridine) (Cas-W-Gly (3)) and Cu(acetylacetonato)(4,4'-dimethyl-2,2'-bipyridine) (Cas-IIIia (4)) to human serum albumin (HSA) by circular dichroism (CD), Electron paramagnetic resonance (EPR) and fluorescence spectroscopy. The results indicate that HSA may bind up to three molecules of the tested Casiopeinas. This is confirmed by inductively coupled plasma atomic absorption spectroscopy measurements of samples of HSA-Casiopeinas after passing by adequate size-exclusion columns. The binding of Cas-II-Gly to HSA was also confirmed by MALDI-TOF mass spectrometric experiments. In the physiological range of concentrations the Casiopeinas form 1:1 adducts with HSA, with conditional binding constants of ca. 1 x 10(9) (1), 4 x 10(7) (2), 1 x 10(6) (3) and 2 x 10(5) (4), values determined from the CD spectra measured, and the fluorescence emission spectra indicates that the binding takes place close to the Trp214 residue. Overall, the data confirm that these Casiopeinas may bind to HSA and may be transported in blood serum by this protein; this might allow some selective tumor targeting, particularly in the case of Cas-Il-Gly. In this work we also discuss aspects associated to the reliability of the frequently used methodologies to determine binding constants based on the measurement of fluorescence emission spectra of solutions containing low concentrations of proteins such as HSA and BSA, by titration with solutions of metal complexes.

2017-10Journal article

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