Sofia Nikolaou

Novel binuclear μ-oxo diruthenium complexes combined with ibuprofen and ketoprofen: Interaction with relevant target biomolecules and anti-allergic potential.

This work presents the synthesis and characterization of two novel binuclear ruthenium compounds of general formula [Ru2O(carb)2(py)6](PF6)2, where py=pyridine and carb are the non-steroidal anti-inflammatory drugs ibuprofen (1) and ketoprofen (2). Both complexes were characterized by ESI-MS/MS spectrometry. The fragmentation patterns, which confirm the proposed structures, are presented. Besides that, compounds 1 and 2 present the charge transfer transitions within 325-330nm; and the intra-core transitions around 585nm, which is the typical spectra profile for [Ru2O] analogues. This suggests the carboxylate bridge has little influence in their electronic structure. The effects of the diruthenium complexes on Ig-E mediated mast cell activation were evaluated by measuring the enzyme β-hexosaminidase released by mast cells stimulated by antigen. The inhibitory potential of the ketoprofen complex against mast cell stimulation suggests its promising application as a therapeutic agent for treating or preventing IgE-mediated allergic diseases. In addition, in vitro metabolism assays had shown that the ibuprofen complex is metabolized by the cytochrome P450 enzymes.

Revisiting oxo-centered carbonyl-triruthenium clusters: investigating CO photorelease and some spectroscopic and electrochemical correlations

We synthesized and characterized a series of oxo-centered carbonyl-triruthenium complexes with the general formula [Ru3O(CH3COO)6(L)2(CO)], where L = 2,6-dimethylpyrazine (dmpz) (1), isonicotinamide (adpy) (2), 4-acetylpyridine (acpy) (3), 3-methylpyridine (3-pic) (4), 4-methylpyridine (4-pic) (5), 4-tert-butylpyridine (4-tbpy) (6), 4-(dimethyl)aminopyridine (dmap) (7), or 4-aminopyridine (ampy) (8); we also investigated the photoreactivity of these complexes. Single-crystal X-ray diffraction helped to elucidate the structures of 1·H2O, 7·C2H4Cl2, and 8. The unit cell of 8 is composed of four cluster units; the hydrogen bonds between the amino groups of the terminal ligand of a neighboring molecule and the oxygen atoms of CO or acetate bridging ligands hold these cluster units together. The spectroscopic (NMR, UV-visible, and IR) and the electrochemical properties (cyclic voltammetry) of these complexes correlated with the ancillary ligands in terms of their σ-donating and π-accepting characteristics. The molecular orbital and the electronic localized description of the [Ru3O]-CO unit helped to rationalize the correlations. The photoreactivity of compounds 1-8 was investigated by laser excitation at 377 nm. Given the CO photorelease quantum yields, σ-donor ligands and aqueous medium (more polar) stabilized the charge-transfer excited state that culminated in CO photosubstitution, leading to higher Φ values.

The role of ancillary ligand substituents in the biological activity of triruthenium-NO complexes

Two novel triruthenium clusters, [Ru3(μ3-O)(μ-OOCCH3)6(NO)L2]PF6 (Lu202f=u202f4‑acetylpyridine, 1, or 4‑tert‑butylpyridine, 2) release NO. Their spectroscopic and electrochemical characterization confirmed their structure. These complexes efficiently deliver NO in solution under irradiation at λirradu202f=u202f377u202fnm and/or through chemical reduction with ascorbic acid. Clusters 1 and 2 elicit vasodilation and, at concentrations of 10-5u202fM, can relax up to 100% of pre-contracted rat aorta. Complex 2 is more cytotoxic to murine melanoma B16F10 cells than complex 1: at 50 times lower concentration than complex 1, complex 2 decreases cell viability to 50% in the dark or under irradiation with visible light (λirradu202f=u202f527u202fnm). The higher cytotoxicity of complex 2 can be assigned to its larger hydrophobicity, promoted by the methylated tert‑butylpyridine ancillary ligand in its structure. Investigation into human serum albumin (HSA) fluorescence quenching by clusters 1 or 2 revealed that complex 2 quenches HSA luminescence with a very high Stern-Vomer constant (KSVu202f=u202f9.49u202f×u202f107u202fM-1 at Tu202f=u202f298u202fK) and suggested that the nature of the interaction between complex 2 and HSA is hydrophobic (ΔHu202f=u202f80.81u202fkJ/mol and ΔSu202f=u202f334.71u202fJ/Ku202fmol). HSA lifetime and circular dichroism data pointed to a static quenching mechanism for both complexes. Together, our results show that a hydrophobic substituent in the cluster ancillary ligand improves NO release ability, cytotoxicity, and interaction with a bio-target.

Method validation and nanoparticle characterization assays for an innovative amphothericin B formulation to reach increased stability and safety in infectious diseases

Graphical abstract Figure. No Caption available. HighlightsNLC‐AmB characterizations employing DLS, AFM, FT‐IR and DSC/TGA demonstrated the nanosized scale of the DDS and evidenced the mechanical encapsulation of the drug.HPLC‐DAD method accurately determined AmB in NLC‐AmB and in receptor solution.Release studies demonstrated AmB sustained release from NLC and pH‐sensitive release was suggested.Encapsulation provided AmB in the least toxic form and it drastically increased the safety of AmB. Abstract Drug Delivery Systems (DDS) of known drugs are prominent candidates towards new and more‐effective treatments of various infectious diseases as they may increase drug bioavailability, control drug delivery and target the site of action. In this sense, the encapsulation of Amphotericin B (AmB) in Nanostructured Lipid Carriers (NLCs) designed with pH‐sensible phospholipids to target infectious tissues was proposed and suitable analytical methods were validated, as well as, proper nanoparticle characterization were conducted. Characterization assays by Dinamic Light Scattering (DLS) and Atomic Force Microscopy demonstrated spherical particles with nanometric size 268.0 ± 11.8 nm and Zeta Potential −42.5 ± 1.5 mV suggestive of important stability. DSC/TGA and FT‐IR assessments suggested mechanical encapsulation of AmB. The AmB aggregation study indicated that the encapsulation provided AmB at the lowest cytotoxic form, polyaggregate. Analytical methods were developed and validated according to regulatory agencies in order to fast and assertively determine AmB in nanoparticle suspension and, in Drug Encapsulation Efficiency (EE%), release and stability studies. The quantification method for AmB in NLC suspension presented linearity in 5.05–60.60 &mgr;g mL−1 range (y = 0.07659x + 0.05344) and for AmB in receptor solution presented linearity in 0.15–10.00 &mgr;g mL−1 range (y = 54609x + 263.1), both with r ≥ 0.999. EE% was approximately 100% and according to the release results, at pH 7.4, a sustained controlled profile was observed for up 46 h. In the meantime, a micellar AmB solution demonstrated an instability pattern after 7 h of contact with the medium. Degradation and release studies under acid conditions (infectious condition) firstly depicted a prominent degradation of AmB (raw‐material), with 20.3 ± 3.5% at the first hour, reaching 43.3 ± 7.0% after 7 h of study. Next, particles faster disruption in acid environment was evidenced by measuring the NLC size variation by DLS and by the loss of the bluish sheen, characteristic of the nanostructured system macroscopically observed. Finally, safety studies depicted that NLC‐AmB presented reduced toxicity in fibroblast cells, corroborating with AmB aggregated form study. Therefore, an innovative AmB formulation was fully characterized and it is a new proposal for in vivo investigations.

New uses for old complexes: The very first report on the trypanocidal activity of symmetric trinuclear ruthenium complexes

This work reports on the trypanocidal activity of a series of symmetric triruthenium complexes combined with azanaphthalene ligands of general formula [Ru3O(CH3COO)6(L)3]PF6 (L=(1) quinazoline (qui), (2) 5-nitroisoquinoline (5-nitroiq), (3) 5-bromoisoquinoline (5-briq), (4) isoquinoline (iq), (5) 5-aminoisoquinoline (5-amiq), and (6) 5,6,7,8-tetrahydroisoquinoline (thiq)). All complexes within the series presented in vitro trypanocidal activity against both the trypomastigote and amastigote forms of T. cruzi. The IC50 values obtained for complexes 1-6 ranged from 1.39 to 165.9μM for the trypomastigote form and from 1.06 to 53.16μM for the amastigote form. These values were lower than the values observed for the metallic core [Ru3O(CH3COO)6(CH3OH)3]+ itself and for the free ligands in all cases. Remarkably, complex 6 displayed lower IC50 values than the reference drug (benznidazole) for the acute (trypomastigote form) and chronic (amastigote form) phases of Chagas disease. These findings, combined with the low toxicity against healthy cells (LLK-MK2 strain) and a high SI value (Selectivity Index >10) make complex 6 an excellent candidate for in vivo tests.