Expression of Tissue Transglutaminase in Human Thyroid Cancer Cell Lines: Effect of Novel Enantiopure Triazole Derivatives

n/

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

Computational mechanistic study of thionation of carbonyl compounds with Lawesson's reagent

The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.This work was supported by the Spanish Ministerio de Economia y Competitividad (MINECO) (Project CTQ2013-44367-C2-1-P), by the Fondos Europeos para el Desarrollo Regional (FEDER), and by the Gobierno de Aragon (Zaragoza, Spain, Bioorganic Chemistry Group, E-10). M.A.C. thanks the University of Catania for partial financial support.Peer Reviewe

Quantum Mechanics Study on Hydrophilic and Hydrophobic Interactions in the Trivaline–Water System

With the aim to elucidate hydrophobic effects in the unfolded state of peptides, DFT-M062X computations on the Val₃H⁺·<i>n</i>H₂O (<i>n</i> up to 22) clusters have been accomplished. As far as the main chain is concerned, four conformers with β-strand and/or polyproline type II conformations, PPII (indicated as β–β, β–PPII, PPII−β, and PPII–PPII), have been found by changing the ϕ and ψ angles. For bare peptide, the side chain (isopropyl) of each residue can independently take on three different orientations with negligible effects on energetics. The great isopropyl spatial separations in β–β and β–PPII conformers allow for the construction of synergic and extensive water–water and water–peptide H-bonding in the minimal hydration Val₃H⁺·22H₂O models without significant steric encumbrance. Conversely, due to the proximity of the isopropyl of the central residue with the other two, some restrictions in the water shell construction around the peptide become evident for the PPII–PPII conformer and the number of energetically accessible structures decreases. This is indicative of correlated motion involving isopropyls and backbone mediated by water molecules, the origin of the nearest neighbor effects. Comparing the thermodynamic data of Ala₃H⁺·22H₂O and Val₃H⁺·22H₂O, what emerges is that both hydration enthalpy and entropy drive the β-strand stability of the latter

Effects of Hydration on the Zwitterion Trialanine Conformation by Electronic Structure Theory

Exploration of interfacial hydration networks of zwitterion and nonionized trialanine has been performed using DFT-M062X quantum chemical computations explicitly considering up to 41 water molecules. The step-by-step water molecules peptide surrounding, carried out for unfolded extended (β), polyproline II (PPII) conformations reveals the crucial importance of explicit solvent effects in stabilizing the zwitterion form and the left-handed PPII-helix ubiquitously found at room temperature for short polyalanines. Hydration effects are much greater for the ionized form of the peptide; thus, the zwitterion is about 10 kcal mol^–1 more stable than the nonionized form. For the β → PPII transformation, the two components of free Gibbs energy act in the opposite direction; thus, it is favored by enthalpy but not by entropy. These findings agree with experimental data that report an equilibrium between these conformers modulated by temperature. Thermodynamic functions of the four conformers (β–β, β–PPII, PPII−β, and PPII–PPII) for zwitterion trialanine are similar to those derived for the protonated one (Ala₃H⁺); therefore, the peptidic conformation is independent of the pH of the solution. Rather, it reflects the high propensity of alanine toward PPII helix. The enthalpic preference of the PPII has electrostatic origin and it is owing to a more favorable interaction of dipole of each peptidic residue with water dipole of H-bonded molecules

BET &amp; 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