Physicochemical Profiling of Sartans: A Detailed Study of Ionization Constants and Distribution Coefficients

A detailed investigation of the ionization and lipophilicity profiles of selected sartans (valsartan, losartan, irbesartan, candesartan, candesartan cilexetil), a class of antihypertensives commonly used in therapy, is presented. The pK_a macroconstants were determined by integrated potentiometry, capillary electrophoresis, and UV spectrophotometry. The measured pK_a macroconstants were connected with the ionizable centers present in each molecule with the aid of model compounds. Potentiometric titrations with the GLpKa apparatus were performed to determine the distribution profile (log D vs. pH) of valsartan, while the shake‐flask procedure was used to characterize the distribution profile of the other compounds. Valsartan showed a lipophilicity profile consistent with the presence of two acidic centers. Losartan and irbesartan, which contain one acidic and one basic center, displayed the classical bell‐shaped profile of ordinary ampholytes. By contrast, a more complex situation emerged in the case of candesartan, due to the large number of ionization equilibria involved. The low solubility of candesartan cilexetil, together with the ease of hydrolysis of the ester moiety, prevented a successful investigation of its ionization and lipophilicity profiles.     

When a worse approximation factor gives better performance: a 3-approximation algorithm for the vertex k-center problem

The vertex k-center selection problem is a well known NP-Hard minimization problem that can not be solved in polynomial time within a \(\rho < 2\) approximation factor, unless \(P=NP\). Even though there are algorithms that achieve this 2-approximation bound, they perform poorly on most benchmarks compared to some heuristic algorithms. This seems to happen because the 2-approximation algorithms take, at every step, very conservative decisions in order to keep the approximation guarantee. In this paper we propose an algorithm that exploits the same structural properties of the problem that the 2-approximation algorithms use, but in a more relaxed manner. Instead of taking the decision that guarantees a 2-approximation, our algorithm takes the best decision near the one that guarantees the 2-approximation. This results in an algorithm with a worse approximation factor (a 3-approximation), but that outperforms all the previously known approximation algorithms on the most well known benchmarks for the problem, namely, the pmed instances from OR-Lib (Beasly in J Oper Res Soc 41(11):1069–1072, 1990) and some instances from TSP-Lib (Reinelt in ORSA J Comput 3:376–384, 1991). However, the \(O(n^4)\) running time of this algorithm becomes unpractical as the input grows. In order to improve its running time, we modified this algorithm obtaining a \(O(n^2 \log n)\) heuristic that outperforms not only all the previously known approximation algorithms, but all the polynomial heuristics proposed up to date.     

A new Phosphorylated Polysaccharide for Biomedical Applications: Generation of 3D Scaffolds with Osteogenic Activity and Coating of Titanium Oxide Surfaces

Summary: A new phosphorylated derivative of carboxymethylcellulose and amidic carboxymethylcellulose containing one phosphate group for each disaccharide unit was synthesized using sodium trimetaphospahte (STMP) as the phosphating agent. The new polysaccharide was characterized by infrared spectroscopy (FT-IR) and the amount of phosphate groups was determined by elemental analysis. These modified polysaccharides were used both to prepare 3D scaffolds and functionalize titanium oxide surfaces with the aim to improve the osseointegration with the host tissue. The presence of phosphate groups modify the physical-chemical properties of the hydrogels with respect to the native ones. The evaluation of the bioactivity of the phosphorylated carboxymethylcellulose hydrogels towards osteoblast-like cells showed a significant increase in the osteocalcin production. The modified surfaces were chemically characterized by means of X-ray photoelectron spectroscopy (XPS) and FT-IR, whereas the surface topography was analysed by Atomic Force Measurements (AFM) measurements before and after the polysaccharide coating. In vitro biological tests using osteoblast-like cells demonstrated that phosphorylated carboxymethylcellulose functionalized TiO₂ surfaces promoted better cell adhesion and significantly enhanced their proliferation. These findings suggest that the phosphate polysaccharide both as a 3D scaffold and as a surface coating promotes osteoblast growth potentially improving the biomaterial osseointegration rate.     

Transient Behavior and Gelation of Free Radical Polymerizations in Continuous Stirred Tank Reactors

Summary: Using the authors' previously developed method for the general kinetic analysis of non‐linear irreversible polymerizations, the simulation of free radical homogeneous polymerization systems with terminal branching and chain transfer to polymer has been carried out for continuous stirred tank reactors. Its improved accuracy on the numerical evaluation of generating functions has been exploited in order to perform their numerical inversion and chain length distributions could also be estimated with or without the presence of gel. A comparison with alternative techniques emphasizing the effect of their simplifying assumptions on the accuracy of calculations is also presented.

Predicted CLD before gelation (t = 1 h), after gelation (t = 15 h, steady state), and close to gel point for a free radical polymerization with transfer to polymer in a CSTR with τ = 60 min.     

Polyions for biocompatible materials

Starting from the thermodynamic properties of some polyamidoamines, showing a protonation behaviour similar to that of small molecules, a relationship with the ability to form polymer-polymer complexes with heparin or heparin-like macromolecules was found. In the light of these results, new heparinisable materials (PUPA and EVAPA) were synthesised, and the surface and bulk structures were understood on the basis of the enhanced hydrophilic characters when these materials are protonated at physiological pH.     

Experimental and theoretical structural study of 2‐pyridyl‐ and 4‐hydroxyphenyl‐1,4‐dihydropyridine derivatives

A series of substituted 1,4‐dihydropyridines (1,4‐DHPs) has been synthesised following the well‐known Hantzsch's procedure for symmetrical 1,4‐DHP. The structures of these compounds have been thoroughly studied by X‐ray crystallographic analysis and semiempirical (AMI) calculations. A good agreement is found between the theoretical and experimental results. In all cases, the most stable conformation fulfils all the requirements needed for exhibiting an antagonist calcium effect.     

Time Programmed Feed of Semi-Batch Reactors with Non-Linear Radical Copolymerizations: An Experimental Study of the System Styrene + Divinylbenzene Using SEC/MALLS

Summary: The radical crosslinking copolymerization of mono and divinyl monomers was experimentally studied with a 2.5 dm³ semi-batch reactor using styrene + divinylbenzene as a model system. The analysis of products was carried out by SEC with a MALLS detector. The influence of the feed policy of divinylbenzene on the time evolution of the copolymer molecular weights and z-average mean square radius of gyration was assessed. A detailed kinetic model, in the absence of intramolecular reactions but taking into account the presence of the two isomers m- and p- in the commercial divinylbenzene and the different reactivities of the various radicals and double bonds was developed; most parameters have been collected from previous kinetic studies, and only two have been regressed using our measured molecular weights. These results can be used to improve the production of branched/crosslinked polymers with controlled molecular architecture.     

Total and free charge densities on mercury coated with self-assembled phosphatidylcholine and octadecanethiol monolayers and octadecanethiol/phosphatidylcholine bilayers

The thermodynamic ‘total’ charge density is the charge to be supplied to the electrode to keep the applied potential constant when the electrode surface is increased by unity, while the extrathermodynamic ‘free’ charge density is the charge actually experienced by the diffuse layer ions. The total charge density at dioleoylphosphatidylcholine (DOPC) and octadecanethiol (ODT) monolayers and mixed ODT/DOPC bilayers self-assembled on mercury from aqueous solutions was determined from chronocoulometric single potential steps to a final potential negative enough to cause complete desorption of the film. The effect of different alkali metal ions and of tetramethylammonium on DOPC desorption was examined. The total charge for ODT monolayers and ODT/DOPC bilayers, +56±3 μC cm⁻², agrees with the value obtained by integration of the current under the reductive desorption voltammetric peaks, only provided the scan rate is higher than 100 mV s⁻¹. An approximate model of the interface of the ODT-coated electrode, which accounts for partial charge transfer from sulfur to mercury and for the degree of dissociation of the sulfhydryl group upon self-assembly, was employed to estimate the free charge density.     

Design and synthesis of a bismethylsulfanyl-steroid-azetyl butanol derivative from 2-nitroestradiol

Several studies for the synthesis of polycyclic derivatives have been reported; however, there is little information on the preparation of steroid-polycyclic derivatives. In this way, the aim of this study was to synthesize a bismethylsulfanyl-steroid-azetyl butanol derivative (compound 10 ) from 2-nitroestrone. The chemical structure was evaluated through both ¹H NMR and ¹³C NMR or spectroscopic analysis. The results showed a good yielding from 10 . It is noteworthy that the reagents used in this investigation are not expensive and do not require special conditions for handling.     

DNA-Targeted NO Release Photoregulated by Green Light

A novel molecular hybrid has been designed and synthesized in which acridine orange (AO) is covalently linked to an N-nitrosoaniline derivative through an alkyl spacer. Photoexcitation of the AO antenna with the highly biocompatible green light results in intense fluorescence emission and triggers NO detachment from the N-nitroso appendage via an intramolecular electron transfer. The presence of the AO moiety encourages the binding with DNA through both external and partially intercalative fashions, depending on the DNA:molecular hybrid molar ratio. Importantly, this dual-mode binding interaction with the biopolymer does not preclude the NO photoreleasing performances of the molecular hybrid, permitting NO to be photogenerated nearby DNA with an efficiency similar to that of the free molecule. These properties make the presented compound an intriguing candidate for fundamental and potential applicative research studies where NO delivery in the DNA proximity precisely regulated by harmless green light is required.