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.     

Busemann functions and equilibrium measures in last passage percolation models

The interplay between two-dimensional percolation growth models and one-dimensional particle processes has been a fruitful source of interesting mathematical phenomena. In this paper we develop a connection between the construction of Busemann functions in the Hammersley last-passage percolation model with i.i.d. random weights, and the existence, ergodicity and uniqueness of equilibrium (or time-invariant) measures for the related (multi-class) interacting fluid system. As we shall see, in the classical Hammersley model, where each point has weight one, this approach brings a new and rather geometrical solution of the longest increasing subsequence problem, as well as a central limit theorem for the Busemann function.     

The two-echelon production-routing problem

This paper introduces the Two-Echelon Production-Routing Problem. This problem is motivated from the petrochemical industry, enlarging the supply chain integration by taking into account production, inventory, and routing decisions in a two-echelon vendor-managed inventory system. We describe, model, and design a branch-and-cut (B&C) to solve the problem under different inventory policies. We also propose a novel exact algorithm, by employing parallel computing techniques, in order to combine local search procedures within a traditional B&C scheme. We evaluate the performance of our methods through extensive computational experiments, both by comparing the algorithms, the effectiveness of the different inventory policies, and the impact of these policies on the partial costs. We derive many managerial insights based on the results. We also validate our new exact algorithm by solving similar problems from the literature, such as the two-echelon multi-depot inventory-routing (2E-MDIRP) and the classical multi-vehicle production-routing problem (MV-PRP). Computational experiments show that our method is very competitive. Based on 512 experiments for the 2E-MDIRP, our algorithm was able to find 111 new best known solutions (BKS), besides proving 412 optimal solutions, against 298 from the literature. For 336 experiments over small and medium size MV-PRP instances, we proved 242 optimal solutions, 11 more than the exact methods from the literature, besides providing 95 new BKS. Moreover, we were the first to tackle large MV-PRP instances exactly, and in this case, our algorithm provides all BKS for instances up to 50 customers, 20 periods and 5 vehicles, outperforming all meta/matheuristics procedures from the literature.     

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.