A practical synthesis of 2,4(5)-diarylimidazoles from simple building blocks

A simple and efficient approach to selectively obtain 2,4(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-arylimidazoles is described. The yield of each of the two products strongly depends on the reaction conditions employed. This reaction provides a simple method to prepare small libraries of biologically active compounds by parallel synthesis.     

Ionization and tautomerization of 2-nitrocyclohexanone in aqueous solution

The keto-enol tautomerism of 2-nitrocyclohexanone (2-NCH) was studied in aqueous solution under different experimental conditions. Ketonization rate constants were measured spectrophotometrically at 25 degrees C at an ionic strength of 0.4 mol dm-3 (NaCl) in diluted hydrochloric acid, in diluted sodium hydroxide, and in several buffers by using NaHSO3 as the scavenger of the keto form. A value of pK(a)(EH) = 4.78 for the enol form was obtained from the rate-pH profile of the reaction. A value of pK(a)(KH) = 5.97 for the keto form was directly obtained from the UV-vis spectra of 2-NCH recorded at different pHs. The equilibrium constant for the keto-enol tautomerism, pK(T) = -log([enol]/[ketone]) = 1.19, was obtained by combining the two pKa values (pK(T) = pK(a)(KH) - pK(a)(EH)). A comparison of these results with the corresponding values (Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley & Sons: New York, 1990; pp 399-480) for cyclohexanone shows the dramatic effects of an alpha-nitro substituent on the keto-enol acidities and the tautomerization constant of alicyclic ketones. Rates and equilibria were discussed in the light of the Br?nsted equation, the principle of nonperfect synchronization, and the Marcus theory. It turns out that, on passing from nitroalkanes to nitroketones, the resonance contribution to pKa and deprotonation rate decreases, being overwhelmed by steric and inductive effects.     

Interactions at the surface of organophilic-modified laponites: a multinuclear solid-state NMR study

Organically modified clays are largely employed in the preparation of nanostructured materials. The structural and dynamic characterization of the clay surface appears very important in the perspective of understanding the molecular mechanisms determining the improvement of the material properties. To this aim, in this work, a synthetic clay, Laponite, was studied in its untreated hydrophilic Na+-form, after ion exchange with alkylammonium cations and after subsequent grafting reaction with an alkoxysilane. These three samples were characterized by IR, SEM, TGA, and X-ray techniques and were deeply investigated by means of a wide combination of 29Si, 13C, and 1H high- and low-resolution solid-state NMR experiments. The grafting reaction with alkoxysilanes, occurring at the clay platelet edges, resulted in a reduction of the clay inter-platelet distances, and in an increased disorder in both the arrangement of the platelets and the conformational structure of the intercalated organic cation chains, probably due to the relative twisting of adjacent platelets.     

Violation of distribution symmetry in statistical evaluation of absolute enantioselective synthesis

Enantiomeric excesses obtained in absolute enantioselective synthesis by chiral autocatalysis (Soai-reaction) were statistically analyzed. Two sets of parallel experiments, which were performed under chemically different conditions, are available. One group contains 37, while the other contains 84 preparative results. The former group shows some interesting tendencies but does not give conclusive statistical results. The sample of 84 parallel experiments, providing 39 R- and 45 S-excesses have shown that these data represent two distinct, non-symmetric sets with different non-Gaussian distributions. Clear S preference was found.     

Computational clues for a new mechanism in the glycosylase activity of the human DNA repair protein hOGG1. A generalized paradigm for purine-repairing systems?

A theoretical density functional theory (DFT, B3LYP) investigation has been carried out on the catalytic cycle responsible for the glycosylase activity of the human DNA repair protein hOGG1: enzyme activation, cleavage of the glycosidic bond, and expulsion of the damaged base. An unprecedented large quantum mechanics (QM) model system has been used, which includes a complete oxoG molecule, the deoxyribose ring bonded to the phosphate groups, and most of the surrounding residues that simulate the protein binding pocket. It has been found that Asp268 does not play any role in Lys249 activation and that the oxoG basis acts as a coenzyme, triggering nucleophile activation by Lys249 deprotonation. An SN2 nucleophilic attack by Lys249 on the anomeric carbon then follows. This is the rate-determining step of the process with an activation barrier of 16.7 kcal mol(-1) in good agreement with the experimental value of 17.1 kcal mol(-1). The expelled oxoG plays again as an enzyme cofactor at the end of the process by activating (via proton transfer) ribose ring opening and Schiff base formation. This study suggests a recurring catalytic strategy in the enzymatic cleavage of purine nucleoside where the activation of the leaving group by protonation of the nucleoside base (via an enzymatic general acid) triggers the cleavage of the glycosidic bond.     

Equilibrium dynamics of an associating polymer melt in narrow slits by computer simulation

Molecular dynamics simulations have been used to study the dynamics of a coarse-grained model of a melt of polymer chains with associating terminal groups, confined in a narrow slit by two layers of Lennard-Jones sites. Simulations were carried out as a function of wall separation and attracting strength. We found that confinement has an important effect on the overall dynamics of the system. Strongly attracting walls can significantly modify the dynamics of the melt, giving an aggregation structure with extremely long relaxation times. A noticeable degree of anisotropy was found for the dynamics of both the individual chains and the aggregates formed by the associating terminal groups.     

Doubly transitive 2‐factorizations

Let be a 2‐factorization of the complete graph K_v admitting an automorphism group G acting doubly transitively on the set of vertices. The vertex‐set V(K_v) can then be identified with the point‐set of AG(n, p) and each 2‐factor of is the union of p‐cycles which are obtained from a parallel class of lines of AG(n, p) in a suitable manner, the group G being a subgroup of A G L(n, p) in this case. The proof relies on the classification of 2‐(v, k, 1) designs admitting a doubly transitive automorphism group. The same conclusion holds even if G is only assumed to act doubly homogeneously. © 2006 Wiley Periodicals, Inc. J Combin Designs     

Simulation and experimental validation of the dynamic behavior of an electromechanically actuated multiple‐disk clutch

Automated multiple‐disk clutches in automotive drivelines are at present hydraulically or electrohydraulically actuated. The electromechanical clutch actuation represents an alternative. The subject of the investigation is a functional model of an electromechanical clutch actuator which consists of a servo motor, a reduction gear and a mechanism for the realization of the force acting on the disks. For the simulation of the dynamic behavior of the electromechanically actuated multiple‐disk clutch a detailed multibody model is developed which includes models of the electromechanical actuator and the wet multiple‐disk clutch. The multiple‐disk clutch is described by coupled partial models for the rotational and translational dynamics. The coupling parameters are the relative disk distances and the forces between the disks. The results of test bench measurements are compared to simulation results. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and β-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.