Zoltán Mucsi

Efficient approach to androstene-fused arylpyrazolines as potent antiproliferative agents. Experimental and theoretical studies of substituent effects on BF3-catalyzed intramolecular [3 + 2] cycloadditions of olefinic phenylhydrazones

Highly diastereoselective Lewis acid induced intramolecular 1,3-dipolar cycloadditions of alkenyl phenylhydrazones (containing various substituents on the aromatic ring) obtained from a d-secopregnene aldehyde were carried out under fairly mild conditions to furnish androst-5-ene-fused arylpyrazolines in good to excellent yields. The ability of phenylhydrazones to undergo cyclization was found to be affected significantly by the electronic features of the substituents on the aromatic moiety. The rates of the ring-closure reactions were observed to be increased by electron-donating and decreased by electron-withdrawing groups. The experimental findings on the BF(3)-catalyzed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory, indicating a noteworthy dependence, mainly of the initial complexation step, and hence of the whole process, on the character of the substituent. The cycloaddition was estimated to occur via a zwitterionic intermediate rather than involving a pure concerted mechanism. The antiproliferative activities of the structurally related pyrazoline derivatives were tested in vitro on three malignant human cell lines (HeLa, MCF7, and A431): the microculture tetrazolium assay revealed that several compounds exerted marked cell growth-inhibitory effects. The highest cytotoxic activities, displayed by the p-methoxyphenylpyrazoline derivative 7d (IC(50) values: 2.01, 2.16, and 1.41 microM on HeLa, MCF7, and A341 cells, respectively), were better than those of cisplatin (IC(50) values: 12.43, 9.63, and 2.84 microM, respectively).

Binding-induced folding transitions in calpastatin subdomains A and C.

Calpastatin, the endogenous inhibitor of calpain, is an intrinsically unstructured protein proposed to undergo folding transitions upon binding to the enzyme. As this feature has never been experimentally tested, we have set out to characterize the conformation of two peptides corresponding to its conserved subdomains, A and C, known to interact with calpain in a Ca2+‐dependent manner. The peptides are disordered in water but show a high propensity for α‐helical conformation in the presence of trifluoroethanol. The conformational transition is sensitive to Ca2+, and is clearly seen upon binding of the peptides to the enzyme. Secondary‐structure prediction of all calpastatin sequences shows that the helix‐forming potential within these regions is a conserved feature of the inhibitor. Furthermore, quantitative data on the binding strength of calpastatin fragments reveal that binding of the inhibitor is accompanied by a large decrease in its configurational entropy. Taken together, these observations point to significant binding‐induced local folding transitions in calpastatin, in a way that ensures highly specific, yet reversible, action of the inhibitor.

Amidicity change as a significant driving force and thermodynamic selection rule of transamidation reactions. A synergy between experiment and theory

Although essential in medicinal and industrial chemistry, transamidation reactions are still poorly understood mechanistically and in particular in terms of the extreme nature for their proceeding either very smoothly or not occurring at all. As yet, there exists no qualitative rule to predict the outcome of an amide interacting with an amine, with quantitative evaluations far from being established. In this paper we aim to clarify the thermodynamic selection rule and driving force of transamidation reactions based on amidicity value, measuring numerically the amide bond strength, toward providing a relatively simple protocol for practicing organic chemists to predict the outcome of an experiment. The change of amidicity over the course of a reaction made it possible to see that the process is favorable or unfavorable. This recently evaluated driving force of amidicity behaves analogously to the driving force of aromaticity in other organic reactions. This paper presents a successful comparison between empirical synthetic results and relevant computational characterizations, for a variety of transamidation reactions, all toward a synergy between experiments and theory. In this paper, we are re-examining experimentally and theoretically earlier experimental findings in relation to transamidation reactions and interpreting them from the aspect of amidicity change and stabilization enthalpies.

Thermodynamic Role of Glutathione Oxidation by Peroxide and Peroxybicarbonate in the Prevention of Alzheimer's Disease and Cancer

First principle quantum molecular computations have been carried out at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory on ethyl mercaptan and diethyl disulfide to study their full conformational space. The consequences of molecular axis chirality for the potential energy hypersurface of diethyl disulfide was fully explored. Thermodynamic functions (U, H, S, and G) have been computed for every conformer of the products as well as the reactants of the redox systems studied. Relative values of the thermodynamic functions were calculated with respect to the reference structures with anti orientation. The energetics of the following Red-Ox reactions Et-SH+HO-OH+HS-Et --> 2H2O+Et-S-S-Et Et-SH+HO-OCOO(-)+HS-Et --> H2O+Et-S-S-Et+HCO3- have been chosen to mimic the biologically important Red-Ox reactions of glutathione G-SH+H2O2+HS-G --> 2H2O+G-S-S-G G-SH+HCO4-+HS-G --> H2O+G-S-S-G+HCO3-. The Red-Ox reaction of Et-SH --> Et-S-S-Et was found to be exothermic by first principle molecular computations and the intramolecular interactions, such as the unusual C-H...H-C noncovalent bondings were studied by Baders atoms in molecules analysis of the electron density topology. The present paper focuses attention on the thermodynamic aspect of the redox reaction of glutathione. It has been noted previously that on going from a cancerous to a healthy cell, the entropy change is negative, corresponding to information accumulation. Likewise, the dissociation of peptide parallel beta-sheets, that dominate the plaques in Alzheimers Disease, governs negative entropy change. It may be interesting to note, according to the results obtained in the present paper, a negative entropy change, corresponding to information accumulation.

Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory.

Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).

Thermodynamic Functions of Molecular Conformations of (2-Fluoro-2-phenyl-1- ethyl)ammonium Ion and (2-Hydroxy-2-phenyl-1-ethyl)ammonium Ion as Models for Protonated Noradrenaline and Adrenaline: First-Principles Computational Study of Conformations and Thermodynamic Functions for the Noradrenaline and Adrenaline Models

This paper reports the structural and thermodynamic consequences of substitution of the OH group by the isoelectronic F-atom in the case of the adrenaline family of molecules. The conformational landscapes were explored for the two enantiomeric forms of N-protonated-beta-fluoro-beta-phenyl-ethylamine, also called (2-fluoro-2-phenyl-1-ethyl)-ammonium ion (Model 1) and that of N-protonated-beta-hydroxy-beta-phenyl-ethylamine, also referred to as (2-hydroxy-2-phenyl-1-ethyl)-ammonium (Model 2) models of noradrenaline and adrenaline molecules. These full conformational studies were carried out by first principles of quantum mechanical computations at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory, using the Gaussian03 program. Also, frequency calculations of the stable structures were performed at the B3LYP/6-31G(d,p), and G3MP2B3 levels of theory. The thermodynamic functions (U, H, S, and G) of the various stable conformations of the title compounds were calculated at these levels of theory for the R and S stereoisomers. Relative values of the thermodynamic functions have been calculated with respect of the chosen reference conformers in which all relevant dihedral angles assumed anti orientation for the Model 1 and Model 2. Through the combination of both point and axis chirality, the enantiomeric and diastereomeric relationships of the six structures for each molecule investigated were established. Intramolecular hydrogen bonding interactions have been studied by the atoms in molecules (AIM) analysis of the electron density. The aromaticity of phenyl group has been determined by a selective hydrogenation protocol. The pattern of the extent of aromacity, due intramolecular interactions, varies very little between the two models studied.

High efficiency two-photon uncaging coupled by the correction of spontaneous hydrolysis

Two-photon (TP) uncaging of neurotransmitter molecules is the method of choice to mimic and study the subtleties of neuronal communication either in the intact brain or in slice preparations. However, the currently available caged materials are just at the limit of their usability and have several drawbacks. The local and focal nature of their use may for example be jeopardized by a high spontaneous hydrolysis rate of the commercially available compounds with increased photochemical release rate. Here, using quantum chemical modelling we show the mechanisms of hydrolysis and two-photon activation, and synthesized more effective caged compounds. Furthermore, we have developed a new enzymatic elimination method removing neurotransmitters inadvertently escaping from their compound during experiment. This method, usable both in one and two-photon experiments, allows for the use of materials with an increased rate of photochemical release. The efficiency of the new compound and the enzymatic method and of the new compound are demonstrated in neurophysiological experiments.