Anti-inflammatory and antioxidant properties of a new arylidene-thiazolidinedione in macrophages.

Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2⁻/⁻ mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2⁺/⁺ cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.

Recent insights on the medicinal chemistry of metal-based compounds: hints for the successful drug design.

Although more complex than usually described, the anticancer action mechanism of cisplatin is based on binding to DNA. Following this line of reasoning, most the metal-based compounds discovered soon after cisplatin were designed to acting as DNA-binding agents and their pharmacological properties were thought to be correlated with this mechanism. Apart from the DNA structure, a significant number of proteins and biochemical pathways have been described as drug targets for metal-based compounds. This paper is therefore aimed at discussing the most recent findings on the medicinal chemistry of metal-based drugs. It starts illustrating the design concept behind the bioinorganic chemistry of anticancer complexes. Anticancer metallic compounds that inhibit the protein kinases are concisely discussed as a case study. The accuracy and limitations of molecular docking programs currently available to predict the binding mode of metallic complexes in molecular targets are further discussed. Finally, the advantages and disadvantages of different in vitro screenings are briefly commented.

Molecular structure of the molybdenum oxo-diperoxo compound MoO(O(2))(2)(OPy)(H(2)O): a computational and X-ray study.

We have carried out a combined experimental and theoretical study of the molecular structure of the MoO(O(2))(2)(OPy)(H(2)O) coordination compound using X-ray crystallography and DFT-B3LYP computational method, respectively. The MoO(O(2))(2)(OPy)(H(2)O) complex crystallizes in the orthorhombic space group Pmna with Z = 4, a = 6.9001(9) A, b = 8.0471(1) A, c = 16.227(2) A, V = 901.0(2) A(3), and the X-ray data analysis yields a bipyramidal-pentagonal coordination polyhedron for the Mo atom. The pyridine N-oxide (OPy) ligand occupies the equatorial position, with the oxygen atom of this ligand being located in the same plane as the four peroxo oxygen atoms. The H(2)O ligand is situated trans to the oxo group, forming intermolecular hydrogen bonds with peroxo groups belonging to two adjacent complexes. In our theoretical approach these intermolecular interactions were taken into account by including two methanol molecules which form hydrogen bonds with the water ligand leading to a good agreement between the calculated and the experimental geometry. Our results suggest that it is necessary to take into account the presence of these interactions in order to reconcile the theoretical results to the experimental data, in particular the distance between Mo and the oxygen of water ligand. These results seem to be a general feature for analogous bis-peroxo complexes that have been reported in the literature.