Synthesis, characterization and pharmacological evaluation of 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one: a new anti-inflammatory compound with reduced gastric ulceration properties

The new compound 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (1), designed using the prodrug approach, was easily obtained in 85% yield and characterized by nuclear magnetic resonance, elemental analysis, mass spectrometry and infrared spectroscopy. The lactam 1 showed anti-inflammatory and analgesic activity comparable to that of the COX-2 inhibitor lumiracoxib, without gastro-ulceration effects. Stability studies demonstrated that the lactam function was stable and did not hydrolyze in pH 1.2 or 7.4. Furthermore, using a thioglycollate-induced peritonitis model, compound 1 was shown to inhibit cell migration by 50.4%, while lumiracoxib inhibited it by 18%. This compound represents a new non-ulcerogenic prototype for the treatment of chronic inflammatory diseases.     

Frustration and hydrophobicity interplay in protein folding and protein evolution

A lattice model is used to study mutations and compacting effects on protein folding rates and folding temperature. In the context of protein evolution, we address the question regarding the best scenario for a polypeptide chain to fold: either a fast nonspecific collapse followed by a slow rearrangement to form the native structure or a specific collapse from the unfolded state with the simultaneous formation of the native state. This question is investigated for optimized sequences, whose native state has no frustrated contacts between monomers, and also for mutated sequences, whose native state has some degree of frustration. It is found that the best scenario for folding may depend on the amount of frustration of the native structure. The implication of this result on protein evolution is discussed.     

Photochemically generated stable cation radical of phenothiazine aggregates in mildly acid buffered solutions

This work characterizes, for the first time, the photochemical behavior of the antipsychotic drugs thioridazine (TR), trifluoperazine (TFP), and fluphenazine (FP) influenced by the aggregation state of the molecules. Samples of monomeric and aggregated forms of phenothiazines were submitted to 20 min of irradiation at 254 nm for intervals of 1, 5, 10, 15, 20, or 25 days. In high phenothiazine concentrations, the irradiation led to the appearance of absorbance bands in the visible region peaking at 633 nm for TR and 509 nm for FP and TFP. In the dark, at room temperature and at 4 degrees C, these bands disappeared, after approximately 15 and approximately 60 min, respectively, but reappeared after a new irradiation session. These visible bands were assigned to stable cation radicals that were characterized by direct EPR measurements and by flash photolysis. Photogenerated stable cation radicals in the phenothiazine aggregates at room temperature are formed probably due to the stacking of the thiazine phenyl moieties. For the monomeric forms of phenothiazines, the spectral changes observed during the irradiation suggested the formation of sulfoxide and hydroxylated derivates. Oxidized derivates were detected by mass spectrometry of the aggregated forms of phenothiazines (>100 microM) only in the samples irradiated for more than 20 days. In contrast, monomeric phenothiazines were totally converted to the oxidized forms after 20 min of irradiation. Surface tension measurements of phenothiazines revealed that, in concentrations above 100 microM, the drugs formed aggregates. In the case of TR, small-angle X-ray scattering measurements indicated that this compound forms large lamellar-like aggregates in aqueous solutions.     

Maximum principle for semi-elliptic trace operators and geometric applications

Based on ideas of L. Alías, D. Impera and M. Rigoli developed in [13], we present a fairly general weak/Omori-Yau maximum principle for trace operators. We apply this version of maximum principle to generalize several higher order mean curvature estimates and to give an extension of Alias-Impera-Rigoli Slice Theorem of [13, Thm. 16 and 21], see Theorems 5 and 6.     

A Six-Armed Phenhomazine Ligand with a Potential “Turn-Off” Copper(II) Sensing Capability through Terbium(III) Luminescence Quenching

Herein, the design, synthesis, and characterization of a phenhomazine ligand are described. The ligand has six pendant acetate arms designed for the combined coordination of copper(II) and lanthanide(III) ions, with the perspective of developing a “turn-off” copper sensor. The key step for the ligand preparation was the one-step endomethylene bridge fission of a diamino Tröger's base with a concomitant alkylation. Fluorescence and absorption spectroscopies as well as nuclear magnetic resonance (NMR) experiments were performed to analyze and understand the coordination properties of the ligand. Transition metal coordination was driven by the synergistic effect of the free nitrogen atoms of the diazocinic core and the two central acetate arms attached to those nitrogen atoms, whereas lanthanide coordination is performed by the external acetate arms, presumably forming a self-assembled 2:2 metallosupramolecular structure. The terbium complex shows the typical green emission with narrow bands and long luminescence lifetimes. The luminescence quenching produced by the presence of copper(II) ions was analyzed. This work sets, therefore, a starting point for the development of a phenhomazine-based “turn-off” copper(II) sensor.     

Synthesis of new porphyrin/fullerene supramolecular assemblies: a spectroscopic and electrochemical investigation of their coordination equilibrium in solution

Two new fullerene ligands have been designed to provide relatively simple frameworks to build supramolecular systems containing both fullerene and Zn-porphyrin moieties. The coordination of the fullerene ligands to the Zn-porphyrin was supported by UV-vis titration, nuclear magnetic resonance and electrochemical data. The resulting spectrophotometric data were processed both graphically and computationally to yield the stoichiometry, stability constant, and molar absorptivity of the species in equilibrium.