Publications by authors named "Jaroslaw Handzlik"

6 Publications

  • Page 1 of 1

The relationship between stereochemical and both, pharmacological and ADME-Tox, properties of the potent hydantoin 5-HTR antagonist MF-8.

Bioorg Chem 2021 01 10;106:104466. Epub 2020 Nov 10.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HTR ligand with antidepressant activity on mice. The combination of DFT calculations of H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HTR affinity and antagonistic action, with K and K values in the range of 3-366 nM and 0.024-99 μM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.
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http://dx.doi.org/10.1016/j.bioorg.2020.104466DOI Listing
January 2021

Formation of active species from ruthenium alkylidene catalysts-an insight from computational perspective.

J Mol Model 2019 Nov 7;25(11):331. Epub 2019 Nov 7.

Faculty of Chemical Engineering and Technology, Cracow University of Technology, ul. Warszawska 24, 31-155, Kraków, Poland.

Ruthenium alkylidene complexes are commonly used as olefin metathesis catalysts. Initiation of the catalytic process requires formation of a 14-electron active ruthenium species via dissociation of a respective ligand. In the present work, this initiation step has been computationally studied for the Grubbs-type catalysts (HIMes)(PCy)(Cl)Ru=CHPh, (HIMes)(PCy)(Cl)Ru=CH-CH=CMe and (HIMes)(3-Br-py)(Cl)Ru=CHPh, and the Hoveyda-Grubbs-type catalysts (HIMes)(Cl)Ru=CH(o-OiPrCH), (HIMes)(Cl)Ru=CH(5-NO-2-OiPrCH), and (HIMes)(Cl)Ru=CH(2-OiPr-3-PhCH), using density functional theory (DFT). Additionally, the extended-transition-state combined with the natural orbitals for the chemical valence (ETS-NOCV) and the interacting quantum atoms (IQA) energy decomposition methods were applied. The computationally determined activity order within both families of the catalysts and the activation parameters are in agreement with reported experimental data. The significance of solvent simulation and the basis set superposition error (BSSE) correction is discussed. ETS-NOCV demonstrates that the bond between the dissociating ligand and the Ru-based fragment is largely ionic followed by the charge delocalizations: σ(Ru-P) and π(Ru-P) and the secondary CHCl, CHπ, and CHHC interactions. In the case of transition state structures, the majority of stabilization stems from London dispersion forces exerted by the efficient CHCl, CHπ, and CHHC interactions. Interestingly, the height of the electronic dissociation barriers is, however, directly connected with the prevalent (unfavourable) changes in the electrostatic and orbital interaction contributions despite the favourable relief in Pauli repulsion and geometry reorganization terms during the activation process. According to the IQA results, the isopropoxy group in the Hoveyda-Grubbs-type catalysts is an efficient donor of intra-molecular interactions which are important for the activity of these catalysts.
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http://dx.doi.org/10.1007/s00894-019-4202-5DOI Listing
November 2019

Hydration in silica based mesoporous materials: a DFT model.

Phys Chem Chem Phys 2016 Dec;18(48):32962-32972

Sorbonne Universités, UPMC Univ Paris 06, UMR 7574, Laboratoire Chimie de la Matière Condensée, Collège de France, 4 place Jussieu, 75252 Paris Cedex 05, France.

The MCM-41 material is very commonly used as a support for catalysts. However, theoretical investigations are significantly limited due to the lack of appropriate models that well and accurately describe the real material and enable effective computation at the same time. In this work, our aim is to obtain calculable models at the DFT level of MCM-41 which are as close as possible to the real material. In particular the hydration degree has been investigated, and we present and characterize here for the first time a model for the MCM-41 unit cell filled with explicit solvent water molecules. This is particularly important, because the models developed here are aimed to be further applied in theoretical ab initio/DFT studies of adsorption or as a support for modelling active sites in catalysts.
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http://dx.doi.org/10.1039/c6cp05460aDOI Listing
December 2016

Characterization of molybdenum monomeric oxide species supported on hydroxylated silica: a DFT study.

Phys Chem Chem Phys 2014 Sep;16(34):18253-60

CNRS-UM2-ENSCM-UM1, UMR 5253, Institut Charles Gerhardt Montpellier, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier, France.

Periodic DFT calculations have been performed on molybdenum(VI) oxide species supported on the hydroxylated amorphous silica surface. The Mo grafting site has been investigated systematically for the type of silanol (geminate, vicinal, isolated or in a nest) accessible on the surface, as well as its effect on H-bond formation and stabilization, with the Mo-oxide species. Different grafting geometries, combined with different degrees of hydration of the Mo species are investigated using atomistic thermodynamics. The most stable Mo(VI) oxide species resulting from these calculations are confronted with experiment. Finally, calculated vibrational frequencies confirm the experimental evidence of the dominant presence of di grafted di-oxo Mo(VI) species on silica up to 700 K.
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http://dx.doi.org/10.1039/c4cp02296cDOI Listing
September 2014

Pharmacophore models based studies on the affinity and selectivity toward 5-HT1A with reference to α1-adrenergic receptors among arylpiperazine derivatives of phenytoin.

Bioorg Med Chem 2011 Feb 5;19(3):1349-60. Epub 2010 Dec 5.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.

The study is focused on (2-alkoxy)phenylpiperazine derivatives of 1-(2-hydroxy-3-(4-arylpiperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione with alkyl or ester substituents at N3 of hydantoin ring, as well as a new designed and synthesized series of compounds with a free N3H group or N3-acetic acid terminal fragment. The compounds were assessed on their affinity for 5-HT(1A) and α(1)-adrenoceptors and evaluated in functional bioassays for antagonistic properties. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) and DFT methods (B3LYP functional, Gaussian 0.3) were used to investigate 3D structure of the compounds. SAR analysis was based on two pharmacophore models, the one described by Barbaro et al. for α(1)-adenoceptor antagonist and the model of Lepailleur et al. for 5-HT(1A) receptor ligands. All compounds exhibited significant to moderate affinities for 5-HT(1A) receptors in nanomolar range (7-610nM). The highest activity (7nM) and selectivity (17.38) for 5-HT(1A) was observed for 1-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (13a). Among new synthesized compounds 1-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione hydrochloride (20a) displayed the highest affinity (16.6nM) and selectivity (5.72) for α(1)-AR.
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http://dx.doi.org/10.1016/j.bmc.2010.11.051DOI Listing
February 2011

Metathesis activity and properties of Mo-alkylidene sites differently located on silica. A density functional theory study.

J Phys Chem B 2005 Nov;109(44):20794-804

Institute of Organic Chemistry and Technology, Cracow University of Technology, ul. Warszawska 24, PL 31-155 Kraków, Poland.

Ethene metathesis proceeding on Mo-methylidene centers on silica is investigated with density functional theory, applying the cluster approach. Three different locations of the active sites are considered, in which the Mo center replaces a pair of geminal silanols, two silanols from adjacent geminal pairs and two single silanols, respectively. It is shown that metathesis activity of the Mo-methylidene sites strongly depends on their location on silica. Different reactivity of the centers toward alkene is explained by differences in their geometrical and electronic structure parameters. The calculated C-H stretching vibrations of the proposed Mo-methylidene, Mo-ethylidene, and molybdacyclobutane surface complexes are well consistent with the reported IR spectra for the corresponding species generated on real molybdena-silica catalysts. On the basis of the obtained results it is proposed that among the studied cases, the Mo centers replacing two silanols from adjacent geminal pairs of silica surface are the most adequate models of the real active sites.
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http://dx.doi.org/10.1021/jp053517bDOI Listing
November 2005
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