Density Functional Theory Calculations: A Useful Tool to Investigate Mechanisms of 1,3-Dipolar Cycloaddition Reactions.

The present review contains a representative sampling of mechanistic studies, which have appeared in the literature in the last 5 years, on 1,3-dipolar cycloaddition reactions, using DFT calculations. Attention is focused on the mechanistic insights into 1,3-dipoles of propargyl/allenyl type and allyl type such as aza-ylides, nitrile oxides and azomethyne ylides and nitrones, respectively. The important role played by various metal-chiral-ligand complexes and the use of chiral eductors in promoting the site-, regio-, diastereo- and enatioselectivity of the reaction are also outlined.

Design of New Schiff Bases and Their Heavy Metal Ion Complexes for Environmental Applications: A Molecular Dynamics and Density Function Theory Study.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

Development of AMBER Parameters for Molecular Simulations of Selected Boron-Based Covalent Ligands.

Boron containing compounds (BCCs) aroused increasing interest in the scientific community due to their wide application as drugs in various fields. In order to design new compounds hopefully endowed with pharmacological activity and also investigate their conformational behavior, the support of computational studies is crucial. Nevertheless, the suitable molecular mechanics parameterization and the force fields needed to perform these simulations are not completely available for this class of molecules. In this paper, Amber force field parameters for phenyl-, benzyl-, benzylamino-, and methylamino-boronates, a group of boron-containing compounds involved in different branches of the medicinal chemistry, were created. The robustness of the obtained data was confirmed through molecular dynamics simulations on ligand/ß-lactamases covalent complexes. The ligand torsional angles, populated over the trajectory frames, were confirmed by values found in the ligand geometries, located through optimizations at the DFT/B3LYP/6-31g(d) level, using water as a solvent. In summary, this study successfully provided a library of parameters, opening the possibility to perform molecular dynamics simulations of this class of boron-containing compounds.

Palladium Iodide Catalyzed Multicomponent Carbonylative Synthesis of 2-(4-Acylfuran-2-yl)acetamides.

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54-81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization.

Chemoselective Oxidation of Isoxazolidines with Ruthenium Tetroxide: A Successful Intertwining of Combined Theoretical and Experimental Data.

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a-c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.

On the size, shape and energetics of the hydration shell around alkanes.

A large number of clathrate-like cages have been proposed as the very first hydration shell of alkanes. The cages include canonical structures commonly found in clathrate hydrates and many others, not previously reported, derived from the carbon fullerene cavities. These structures have a rich and variegated form, which can adapt to the shape and conformation of the solute. They avoid "wasting" hydrogen bonds, while minimizing the volume cage and maximizing the solute-solvent van der Waals interactions. DFT/M06-2X and MP2 ab initio calculations give comparable structural and energetic results although the latter predicts slightly larger cages for a given solute. It is shown that the van der Waals interactions are substantial and the large exoenergetic values found for isobutane and cyclopentane provide an explanation for the surprising high melting points of related hydrates at room pressure. The encaging enthalpy for various hydrocarbons is similar to the enthalpy of solution measured at a temperature just above the melting point of aqueous hydrocarbon solutions, thus indicating that water molecules should not deviate too much from the configuration with O-H bonds tangentially oriented with respect to the solute surface. The computed trend differs from the enthalpy of solution measured at room temperature, thus the very first hydration shell departs, up to a certain degree, from the clathrate-like structures.

Amyloid-Beta Induces Different Expression Pattern of Tissue Transglutaminase and Its Isoforms on Olfactory Ensheathing Cells: Modulatory Effect of Indicaxanthin.

Herein, we assessed the effect of full native peptide of amyloid-beta (Aß) (1-42) and its fragments (25-35 and 35-25) on tissue transglutaminase (TG2) and its isoforms (TG2-Long and TG2-Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre-treatment with indicaxanthin from Opuntia ficus-indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O2-), and apoptotic pathway activation was assessed. The levels of Nestin and cyclin D1 were also evaluated. Our findings highlight that OECs exposure to Aß(1-42) and its fragments induced an increase in TG2 expression levels and a different expression pattern of its isoforms. Indicaxanthin pre-treatment reduced TG2 overexpression, modulating the expression of TG2 isoforms. It reduced total ROS and O2- production, GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also induced an increase in the Nestin and cyclin D1 expression levels. Our data demonstrated that indicaxanthin pre-treatment stimulated OECs self-renewal through the reparative activity played by TG2. They also suggest that Aß might modify TG2 conformation in OECs and that indicaxanthin pre-treatment might modulate TG2 conformation, stimulating neural regeneration in Alzheimer's disease.

Synthesis and Biological Evaluation of 2,3,4-Triaryl-1,2,4-oxadiazol-5-ones as p38 MAPK Inhibitors.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

A Zinc-Mediated Deprotective Annulation Approach to New Polycyclic Heterocycles.

A straightforward approach to new polycyclic heterocycles, 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, is presented. It is based on the ZnCl2-promoted deprotective 6-endo-dig heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (CH2Cl2, 40 °C for 3 h). The zinc center plays a dual role, as it promotes Boc deprotection (with formation of the tert-butyl carbocation, which can be trapped by substrates bearing a nucleophilic group) and activates the triple bond toward intramolecular nucleophilic attack by the carbamate group. The structure of representative products has been confirmed by X-ray diffraction analysis.

Novel 3,3-disubstituted oxindole derivatives. Synthesis and evaluation of the anti-proliferative activity.

3,3-Disubstituted oxindole derivatives bearing a nitrogen atom at the C-3 position have been synthesized starting from 3-alkyl oxindole through a metal free pathway. These derivatives have been tested in five human tumor cell lines (PC3, MCF7, SW620, MiaPaca2 and A375) and on primary cells (PBMCs) from healthy donors providing compound 6d showing a strong anticancer effect in all cancer lines on the low micromolar range.

1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: synthesis and biological evaluation.

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 µM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.

Transient and intermediate carbocations in ruthenium tetroxide oxidation of saturated rings.

The ruthenium tetroxide-mediated oxidation of cyclopentane, tetrahydrofuran, tetrahydrothiophene and N-substituted pyrrolidines has been studied computationally by DFT and topological (analysis of the electron localization function, ELF) methods. In agreement with experimental observations and previous DFT calculations, the rate-limiting step of the reaction takes place through a highly asynchronous (3 + 2) concerted cycloaddition through a single transition structure (one kinetic step). The ELF analysis identifies the reaction as a typical one-step-two-stages process and corroborates the existence of a transient carbocation. In the case of pyrrolidines, the carbocation is completely stabilized as an energy minimum in the form of an iminium ion and the reaction takes place in two steps.

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (-9.65 and -10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Quantum Mechanics Approach to Hydration Energies and Structures of Alanine and Dialanine.

A systematic approach to the phenomena related to hydration of biomolecules is reported at the state of the art of electronic-structure methods. Large-scale CCSD(T), MP4-SDQ, MP2, and DFT(M06-2X) calculations for some hydrated complexes of alanine and dialanine (Ala⋅13 H2 O, Ala2 H+ ⋅18 H2 O, and Ala2 ⋅18 H2 O) are compared with experimental data and other elaborate modeling to assess the reliability of a simple bottom-up approach. The inclusion of a minimal number of water molecules for microhydration of the polar groups together with the polarizable continuum model is sufficient to reproduce the relative bulk thermodynamic functions of the considered biomolecules. These quantities depend on the adopted electronic-structure method, which should be chosen with great care. Nevertheless, the computationally feasible MP2 and M06-2X functionals with the aug-cc-pVTZ basis set satisfactorily reproduce values derived by high-level CCSD(T) and MP4-SDQ methods, and thus they are suitable for future developments of more elaborate and hence more biochemically significant peptides.

BET & ELF Quantum Topological Analysis of Neutral 2-Aza-Cope Rearrangement of γ-Alkenyl Nitrones.

The 2-Aza-Cope rearrangement of γ-alkenyl nitrones is a rare example of the neutral thermal 2-aza-Cope process that usually takes place with cationic species. During the rearrangement, a redistribution of bonds and electronic density occurs in one kinetic step. However, the introduction of substituents with different steric requirements and electronic features might alter the activation energies and the synchronicity of the reaction. The electron localization function (ELF) analysis and its application to Bonding Evolution Theory (BET) analysis within the context of Molecular Electron Density Theory (MEDT) is an excellent tool to monitor the electron density along the reaction coordinate and thus investigate in detail bond breaking and formation and the corresponding energy barriers. By analyzing topological ELF calculations of seventeen 2-aza-Cope nitrone rearrangements with selected substituents, the main factors influencing the synchronicity of the process were investigated. This MEDT study results revealed that the rearrangement is a non-polar process mostly influenced by steric factors rather than by electronic ones, and confirms the pseudoradical character of the process rather than any pericyclic electron-reorganization.

Synthesis of spiro[isoindole-1,5'-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction.

A series of spiro[isoindole-1,5-isoxazolidin]-3(2H)-ones has been synthesized by 1,3-dipolar cycloaddition of N-benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9-22 µM. Biological tests suggest that the antitumor activity could be linked to the inhibition of the protein-protein p53-MDM2 interaction. Docking measurements support the biological data.

Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles.

A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively.

Interfacial water at the trialanine hydrophilic surface: a DFT electronic structure and bottom-up investigation.

DFT-M062X quantum chemical computations on the Ala3H(+)·nH2O (n up to 37) complexes have been performed to model for hydration effects on the molecular properties of protonated trialanine. Following simple rules to arrange water molecules around the peptide, geometry optimization allows us to find four minima corresponding to the unfolded extended (ß) and polyproline II (PPII) conformations. The peptide is incorporated into the network of hydrogen bonds of interfacial water molecules with a hydration energy of about -85 kcal mol(-1). The progressive hydration of the peptide shows a more efficient intermolecular hydrogen bonding in the PPII arrangement, and the following relative electronic energy stability ß-ß < ß-PPII ≈ PPII-ß < PPII-PPII has been found. The conformational entropy term proceeds in the reverse direction, thus these changes compensate in a way that leads to small changes in Gibbs free energy. These findings agree with experimental data which report an equilibrium between these conformers modulated by temperature.

Synthesis and biological properties of 5-(1H-1,2,3-triazol-4-yl)isoxazolidines: a new class of C-nucleosides.

A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches the 50% in HepG2 and HT-29 cells and increases up to 56% in the SH-SY5Y cell line after 72 h of incubation at a 100 µM concentration.

C-5'-Triazolyl-2'-oxa-3'-aza-4'a-carbanucleosides: Synthesis and biological evaluation.

A novel series of 2'-oxa-3'-aza-4'a-carbanucleosides, featured with a triazole linker at the 5'-position, has been developed by exploiting a click chemistry reaction of 5'-azido-2'-oxa-3'-aza-4'a-carbanucleosides with substituted alkynes. Biological tests indicate an antitumor activity for the synthesized compounds: most of them inhibit cell proliferation of Vero, BS-C-1, HEp-2, MDCK, and HFF cells with a CC50 in the range of 5.0-40 µM. The synthesized compounds do not show any antiviral activity.