Overcoming Multidrug Resistance (MDR): Design,Biological Evaluation and Molecular Modelling Studies of 2,4-Substituted Quinazoline Derivatives

Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC₅₀ values in the nanomolar range ( 1 d , 1 e , 2 a , 2 c , 2 e ). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.     

Interaction of inositol phosphate with calcite

The interaction of myo-inositol hexaphosphate with calcite was studied to evaluate the adsorption mechanisms and the electrochemical modifications induced by interaction of a molecule at such a high-charge density. In addition to quantitative information through the construction of adsorption isotherms, FT-IR and Laser Doppler Velocimetry - Photon Correlation Spectroscopy (LDV-PCS) were employed to investigate the nature of the adsorbent-adsorbate bonds and to determine the electrophoretic mobility and size of the particles before and after sorption. The experiments were also run with orthophosphate (Pi) for comparison. The amount of sorbed P increased to reach a plateau at 17.8 mol m^-2 for inositol hexaphosphate (IHP) while for Pi rose 1.4 mol m^-2 but at C_e > 610^-4 M it had a sharp increase reaching 155 mol m^-2. As expected, for Pi, adsorption predominated up Ce 610^-4 M by covering about 20% of total surface. The adsorption occurred at sites that behaved as nucleus of formation of the clustering of Ca- and PO₄-ions with the ending formation of calcium phosphate precipitates at C_e higher than 610^-4 M. The reaction of inositol hexaphosphate with calcite involves, besides adsorption, precipitation of Ca salts and hence calcite dissolution also at the lowest added IHP concentrations, accounting for the large amount retained by calcite. Sorption of IHP on calcite caused aggregation of particles at low concentrations followed by an increase of their negative charge and hence re-dispersion at higher concentrations. These results indicate a great IHP-fixing capacity of calcite that can affect its accumulation in soils and P bioavailability, and a considerable change of calcite electrochemical properties and particle size distribution that can modify aggregate stability.     

Cathodic protection of carbon steel in natural seawater: Effect of sunlight radiation

Cathodic protection of metals in seawater is known to be influenced by chemical–physical parameters affecting cathodic processes (oxygen discharge, hydrogen evolution and calcareous deposit precipitation). In shallow seawater, these parameters are influenced by sunlight photoperiod and photosynthetic activity. The results presented here represent the first step in studies dedicated to cathodic protection in shallow photic seawater. This paper reports on carbon steel protected at −850 mV vs. Ag/AgCl (oxygen limiting current regime) in the presence of sunlight radiation but in the absence of biological and photosynthetic activity, the role of which deserves future research. Comparison of results obtained by exposing electrochemical cells to daylight cycles in both biologically inactivated natural seawater and in NaCl 3.5 wt.% solutions showed that sunlight affects current densities and that calcareous deposit interfere with light-currents effects. Sunlight radiation and induced heating of the solution have been separated, highlighting results not otherwise obvious: (1) observed current waves concomitant with sunlight radiation depend fundamentally on solar radiation, (2) solar radiation can determine current enhancements from early to late phases of aragonite crystal growth, (3) a three-day-old CaCO₃ layer reduces but does not eliminate the amplitude of the current waves. Theoretical calculations for oxygen limiting currents and additional field tests showed that sunlight, rather than bulk solution heating, is the main cause of daily current enhancements. This was confirmed by polarizations performed at −850 and −1000 mV vs. Ag/AgCl (constant bulk temperature), during which the electrode was irradiated with artificial lighting. This test also confirmed O₂ discharge to be the cathodic process involved. A mechanism of radiation conversion to heat in the oxygen diffusion layer region is proposed.     

An experimental comparison of a graphite electrode and a gas diffusion electrode for the cathodic production of hydrogen peroxide

This work studies the production of hydrogen peroxide through the cathodic reduction of oxygen in acidic medium, by comparing the results obtained using a commercial graphite and a gas diffusion electrode. A low pH was required to allow the application of hydrogen peroxide generation to an electro-Fenton process. The influence of applied potential and the gas flow composition were investigated. The gas diffusion electrode demonstrates a higher selectivity for hydrogen peroxide production, without significantly compromising the iron regeneration, thus making its successful application to a cathodic Fenton-like treatment, possible. Unlike the graphite cathode, the gas diffusion cathode also proved to be effective in the air flow.     

Pt–Ba–Al2O3 for NOx storage and reduction: Characterization of the dispersed species

Pt–Ba–Al₂O₃ active and selective for NO_x storage and selective reduction to N₂ has been prepared and tested. Characterization of the parent Al₂O₃, Pt–Al₂O₃ and Ba–Al₂O₃ materials, as well as of Pt–Ba–Al₂O₃ catalyst in the oxidized, reduced and sulphated state has been performed by FT-IR spectroscopy of low-temperature adsorbed carbon monoxide and of adsorbed acetonitrile. XRD, TEM and XPS analyses have also been performed. Evidence for the predominance of Ba species, which are highly dispersed on the alumina support surface, and may be carbonated or sulphated, has been provided. Competitive interaction of Pt and Ba species with the surface sites of alumina has also been found.     

Anodic,cathodic and combined treatments for the electrochemical oxidation of an effluent from the flame retardant industry

The electrochemical oxidation of an effluent from the manufacture of phosphorus based flame retardants was studied. To reach a residual concentration of reduced phosphorus lower than 10 mg L⁻¹, in compliance with Italian law for industrial wastewater disposal, anodic oxidation using a boron-doped diamond (BDD) anode and electro-Fenton (EF) treatment were tested. The effects of some factors are optimised and a comparison of the reaction pathways is also presented. A combined treatment using EF with BDD conducted in an undivided cell is shown not to enhance the data obtained with BDD while a novel combined treatment using EF and BDD in a divided cell shows promising results when an anionic membrane is used as separation. In this last case the cell operates as two different batch reactors working with the same current. The anodic compartment, fed with raw effluent, provides partial oxidation, while the cathodic compartment, fed with the partially anodically oxidised solution, completes the treatment. When the effluent is transferred in the cathodic compartment, the anodic one is fed with fresh untreated solution. The advantage of this kind of coupling consists in the simultaneity of the two treatments which allows total oxidation with notable saving of charge and time.     

Coupling Interrupted Fischer and Multicomponent Joullié-Ugi to Chase Chemical Diversity: from Batch to Sustainable Flow Synthesis of Peptidomimetics

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié-Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space-time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié-Ugi-type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.