Michal Malček

Copper(II) complexes with new fluoroquinolones: Synthesis, structure, spectroscopic and theoretical study, DNA damage, cytotoxicity and antiviral activity.

Copper(II) complexes with fluoroquinolones in the presence of the nitrogen donor heterocyclic ligands 1,10-phenanthroline have been considered in detail. The phenanthroline moiety was introduced into the ligand environment with the aim to determine whether the nuclease activity is feasible. All suitable X-ray structures of the complexes under study reveal a distorted square pyramidal coordination geometry for Cu(II) atom. The conformational and spectroscopic (FT-IR and UV-visible) behavior has been analyzed and has been interpreted with respect to B3LYP/6-311G* calculations including molecular dynamics. The ability of the complexes to cleave DNA was studied by agarose gel electrophoresis with plasmid DNA pBSK+. The results have confirmed that the complexes under study behave as the chemical nucleases. Nuclease like activity in the absence of hydrogen peroxide allows us to deduce an interaction of the complexes with the DNA resulting in the conversion of supercoiled circular DNA to the nicked form. The DNA cleavage activity enhanced by the presence of hydrogen peroxide demonstrates the participation of reactive oxygen species, such as superoxide radical anions and hydroxyl radicals which presence was confirmed independently using the standard radical scavenging agents. It has been suggested that the radical formation through the Fenton/Haber-Weiss reaction is mediated by the redox cycling mechanisms with the participation of cupric/cuprous ions. Cytotoxic activity was evaluated as the 50% cytotoxic concentration (CC50). The potential effects of tested compounds on replication of murine gammaherpesvirus 68 (MHV-68) under in vitro conditions were also evaluated. However, no antiviral activity against MHV-68 was observed.

Conformational, spectroscopic, and molecular dynamics DFT study of precursors for new potential antibacterial fluoroquinolone drugs.

Biological activity, functionality, and synthesis of (fluoro)quinolones is closely related to their precursors (for instance 3-fluoroanilinoethylene derivatives) (i.e., their functional groups, conformational behavior, and/or electronic structure). Herein, the theoretical study of 3-fluoroanilinoethylene derivatives is presented. Impact of substituents (acetyl, methyl ester, and ethyl ester) on the conformational analysis and the spectral behavior is investigated. The B3LYP/6-311++G** computational protocol is utilized. It is found that the intramolecular hydrogen bond N-H···O is responsible for the energetic preference of anti (a) conformer (anti position of 3-fluoroanilino group with respect to the C═C double bond). The Boltzmann ratios of the conformers are related to the differences of the particular dipole moments and/or their dependence on the solvent polarity. The studied acetyl, ethyl ester, and methyl ester substituted fluoroquinolone precursors prefer in the solvent either EZa, ZZa, or both conformers equally, respectively. In order to understand the degree of freedom of rotation of the trans ethyl ester group, B3LYP/6-311G** molecular dynamic simulations were carried out. Vibrational frequencies, electron transitions, as well as NMR spectra are analyzed with respect to conformational analysis, including the effect of the substituent. X-ray structures of the precursors are presented and compared with the results of the conformational analysis.

Redox processes of 2,6-dichlorophenolindophenolate in different solvents. A combined electrochemical, spectroelectrochemical, photochemical, and theoretical study

Cyclic voltammetric and EPR/UV-vis-NIR spectroelectrochemical studies were performed to examine the cathodic reduction of 2,6-dichlorophenolindophenolate (DCIP) in proton-donating aqueous and methanol solutions, as well as in aprotic dimethylsulfoxide (DMSO), and to characterize the paramagnetic species generated upon the DCIP reduction. In situ EPR and UV-vis-NIR spectroelectrochemistry confirmed the formation of the radical anion DCIP•– in DMSO and methanol. The same radical anion was found also in the reaction system consisting of KO2 mixed under argon with DCIP in DMSO or methanol, evidencing the electron transfer from superoxide radical anion to DCIP. The expected radical anion DCIP•– was not detected in the photoexcited suspensions DCIP/TiO2/DMSO under argon, which indicates fast consecutive reactions of photogenerated DCIP•– in the vicinity of TiO2 surface. The reduction of blue-color DCIP to the final colorless product DCIPH2 can be realized in multiple reaction pathways determined mainly by the proton-donating capacity of the solvent. Following the calculated total DFT energies, the oxygen on the indophenol moiety represents the first proton acceptor site for DCIP, DCIP•–, as well as for DCIP2– species.

Calculations of hyperfine coupling constant of copper(II) in aqueous environment. Finite temperature molecular dynamics and relativistic effects

AbstractThe presented paper is focused on the calculation of hyperfine coupling constants (HFCC) of Cu2+ ion in water environment. To simulate the conditions of the electron paramagnetic resonance (EPR) experiment in aqueous phase, molecular dynamics using the density functional theory (DFT) was employed. In total three different functionals (BLYP, B3LYP, M06) were employed for studying their suitability in describing coordination of Cu2+ by water molecules. The system of our interest was composed of one Cu2+ cation surrounded by a selected number (between thirty and fifty) of water molecules. Besides the non-relativistic HFCCs (Fermi contact terms) of Cu2+ also the four-component relativistic HFCC calculations are presented. The importance of the proper evaluation of HFCCs, the inclusion of spin-orbit term, for Cu2+ containing systems (Neese, J. Chem. Phys. 118, 3939 2003; Almeida et al., Chem. Phys. 332, 176 2007) is confirmed at the relativistic four-component level of theory.n Graphical AbstractFive and six coordinated copper dication is solvated by adding extra water molecules to simulate conditions in aqueous solution. Molecular dynamics study is performed and nonrelativistic and relativistic hyperfine coupling constants are calculated subsequently.

Protonation and electronic structure of 2,6-dichlorophenolindophenolate during reduction. A theoretical study including explicit solvent

AbstractProtonation in the two-electron/two-proton reduction processes of 2,6-dichlorophenolindophenolate (DCIP) is investigated combining density functional theory (DFT) and molecular dynamics (MD) methods. DCIP (anion), DCIP•– (radical anion), and DCIP2− (dianion) are considered, including the electronic structure analysis from the prospective of quantum theory of atoms and molecules (QTAIM). It is shown that oxygen on the indophenolate moiety and nitrogen are the first and/or the second proton acceptor sites and their energetic order depends on the total charge of the system. MD simulations of differently charged species interacting with the solvent molecules have been performed for methanol, water, and oxonium cation (H3O+). Methanol and water molecules are found to form only hydrogen bonds with the solute irrespective of its charge. The calculated pKa values show that the imino group of DCIPH− is a weaker acid than water. While in the case of DCIP (and DCIP•–) plus oxonium cation, proton transfer from the solvent to the solute was evidenced for both aforementioned acceptor sites. In addition, MD simulations of bulks containing 15 and 43 molecules of water around the DCIP molecule have been performed, revealing the formation of 2–4 hydrogen bonds.n Graphical Abstract2,6-Dichlorophenolindophenolate interacts with solvent molecules (water, oxonium cation and methanol). Hydrogen transfer and electronic structure are studied by DFT and molecular dynamics methods

NO Releasing and Anticancer Properties of Octahedral Ruthenium–Nitrosyl Complexes with Equatorial 1H-Indazole Ligands

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)4(NO)]Cl2·H2O ([3]Cl2·H2O) and trans-[RuOH(Hind)4(NO)]Cl2·H2O ([4]Cl2·H2O), have been prepared from trans-[Ru(NO2)2(Hind)4] ([2]). When the pH-dependent solution behavior of [3]Cl2·H2O and [4]Cl2·H2O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)2(Hind)2(NO)] ([5]) and [RuOH(ind)2(Hind)2(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, 1H NMR) techniques. Compound [2], as well as [3]Cl2·2(CH3)2CO, [4]Cl2·2(CH3)2CO, and [5]·0.8CH2Cl2, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl2 and [4]Cl2 was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl2 and [4]Cl2 showed considerable antiproliferative activity in human cancer cell lines with IC50 values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl2 and [4]Cl2 was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.

Finite nucleus effects, relativistic effects and picture change error in the IOTC/DKH2 contact spin densities of Cu, Ag, Au atoms

Abstract Sensitivity of contact spin density as well as electron density to the size of nucleus is investigated using the Gaussian model of nucleus and the point charge nucleus model. Scalar Infinite Order Two Component and scalar second order Douglas-Kroll-Hess quasirelativistic contact spin densities (spin densities at the nucleus) of Cu, Ag and Au atoms are considered. The non-relativistic contact spin densities and the valence s-orbital contact densities of Kramers restricted orbitals (Cu, Ag, Au atoms) are presented as well. The picture change error in the quasirelativistic calculations of spin densities is corrected by analytic means. Uncontracted triple-zeta UTZ+Ns basis sets are employed, where N is the number of additional tight s Gaussians. In addition, the impact of tight p and d Gaussians is briefly discussed.

Calculations of hyperfine coupling constant of the TMPD molecule

Calculations of hyperfine coupling constant of the TMPD molecule The calculations of the hyperfine coupling constants (HFCC) of tetramethyl-p-Phenylenediamine (TMPD) are presented. Several DFT functionals are employed and the results are compared with the UHF and MP2 level of theory. Sensitivity of HFCC to the choice of the basis set is investigated. Impact of the different conformers of TMPD and the equivalence of methyl group hydrogens on the HFCC values is considered. The solvent effects are introduced via polarizable continuum model and compared with in vacuo calculations. Last but not least, molecular dynamics is employed to include the solvent molecules as well as the dynamics explicitly, accounting similar conditions comparing to the liquid phase EPR experiment.