Maura Malińska

PEGylated Nanoceria as Radical Scavenger with Tunable Redox Chemistry

We report the direct synthesis of cerium oxide nanoparticles (CNPs) in polyethylene glycol (PEG) based solutions with efficient radical scavenging properties. Synthesis of CNPs in PEG demonstrated a concentration dependent (of PEG) redox activity characterized by UV-visible spectroscopy. PEGylated CNPs acted as efficient radical scavengers, and superoxide dismutase (SOD) activity of CNPs synthesized in various concentration of PEG did not reduce compared to bare nanoceria. In addition to superoxide, PEGylated nanoceria demonstrated quenching of peroxide radicals as well. It was observed that the reaction with hydrogen peroxide leads to the formation of a charge transfer complex governed by the concentration of PEG. The stability of the charge transfer complex provides the tunable oxidation state of CNPs. The stability of this complex influences the regenerative capacity of the active 3+ oxidation state of CNPs. The cell viability as well as SOD activity of PEGylated CNPs is compared to those of bare CNPs, and the differences are outlined.

Batchwise and Continuous Nanofiltration of POSS-Tagged Grubbs–Hoveyda-Type Olefin Metathesis Catalysts

New molecular-weight-enlarged metathesis catalysts, which bear polyhedral oligomeric silsesquioxane (POSS) tags, were synthesized and characterized. The catalysts can be recovered from the reaction mixture by using nanofiltration techniques and can be reused. It was found that the membranes Starmem 228 and PuraMem 280 successfully separate the catalyst from the post-reaction mixtures to below 3 ppm. The application of these POSS-tagged catalysts in a continuous metathesis reaction was also investigated.

Statistical analysis of multipole-model-derived structural parameters and charge-density properties from high-resolution X-ray diffraction experiments.

A comprehensive analysis of various properties derived from multiple high-resolution X-ray diffraction experiments is reported. A total of 13 charge-density-quality data sets of α-oxalic acid dihydrate (C2H2O4·2H2O) were subject to Hansen-Coppens-based modelling of electron density. The obtained parameters and properties were then statistically analysed yielding a clear picture of their variability across the different measurements. Additionally, a computational approach (CRYSTAL and PIXEL programs) was utilized to support and examine the experimental findings. The aim of the study was to show the real accuracy and interpretation limits of the charge-density-derived data. An investigation of raw intensities showed that most of the reflections (60-70%) fulfil the normality test and the lowest ratio is observed for weak reflections. It appeared that unit-cell parameters are determined to the order of 10(-3) Å (for cell edges) and 10(-2) ° (for angles), and compare well with the older studies of the same compound and with the new 100 K neutron diffraction data set. Fit discrepancy factors are determined within a 0.5% range, while the residual density extrema are about ±0.16 (3) e Å(-3). The geometry is very well reproducible between different data sets. Regarding the multipole model, the largest errors are present on the valence shell charge-transfer parameters. In addition, symmetry restrictions of multipolar parameters, with respect to local coordinate systems, are well preserved. Standard deviations for electron density are lowest at bond critical points, being especially small for the hydrogen-bonded contacts. The same is true for kinetic and potential energy densities. This is also the case for the electrostatic potential distribution, which is statistically most significant in the hydrogen-bonded regions. Standard deviations for the integrated atomic charges are equal to about 0.1 e. Dipole moments for the water molecule are comparable with the ones presented in various earlier studies. The electrostatic energies should be treated rather qualitatively. However, they are quite well correlated with the PIXEL results.

Physicochemical Characteristics of Sunitinib Malate and its Process-Related Impurities

In this article, details of crystal and molecular structures of sunitinib malate (SUM), an anticancer therapeutic, and its key synthetic intermediate are presented. Both these compounds were also characterized spectroscopically and thermally. SUM crystallizes in the monoclinic P2(1) space group with two molecules in the asymmetric part of the unit cell, whereas the intermediate crystallises in the triclinic P-1 space group with four independent molecules in the asymmetric unit. The three-dimensional structure of SUM consists of two different layers of molecules. The first one is built of the malic anions, whereas the other layer consists of more hydrophobic sunitinib molecules. This layer is formed by two types of molecules creating a herring bond-like pattern with pairs of neighboring cations forming the V-shape arrangement of molecules. The V-shaped pairs of molecules form ribbons by fitting into two neighboring V shapes. The characteristic V-shape assemble of the moieties is hold together with three C-H…F weak interactions. Besides, process-related impurities of SUM were identified and their structures confirmed by separate synthesis. These impurities were fully characterized by spectroscopic and crystallographic methods as well as by differential scanning calorimetry and thermogravimetric analysis. The H-, (13)C-, and (15)N-nuclear magnetic resonance signals were fully assigned structurally and the resulting structures were confirmed by Fourier-transformed infrared spectroscopy. It was the herein elaborated synthesis of impurity-free SUM that allowed for growing of its single crystals suitable for X-ray crystallographic studies. Comparison of the powder X-ray diffraction pattern for SUM with that derived from single-crystal X-ray crystallographic analysis indicated that SUM formed the polymorph I crystal phase, which is also encountered in its pharmaceutical formulation.

Mechanistic Studies of Hoveyda–Grubbs Metathesis Catalysts Bearing S‐, Br‐, I‐, and N‐coordinating Naphthalene Ligands

Derivatives of the Hoveyda-Grubbs complex bearing S-, Br-, I-, and N-coordinating naphthalene ligands were synthesized and characterized with NMR and X-ray studies. Depending on the arrangement of the coordinating sites on the naphthalene core, the isomeric catalysts differ in activity in model metathesis reactions. In particular, complexes with the RuCH bond adjacent to the second aromatic ring of the ligand suffer from difficulties experienced on their preparation and initiation. The behavior most probably derives from steric hindrance around the double bond and repulsive intraligand interactions, which result in abnormal chemical shifts of benzylidene protons observed with (1) H NMR. Furthermore EXSY studies revealed that the halogen-chelated ruthenium complexes display an equilibrium, in which major cis-Cl2 structures are accompanied with small amounts of isomeric forms. In general, contents of the minor forms, measured at 80 °C, correlate with the observed activity trends of the catalysts, although some exceptions complicate the mechanistic picture. We assume that for the family of halogen-chelated metathesis catalysts the initiation mechanism starts with the cis-Cl2 ⇌trans-Cl2 isomerization, although further steps may become rate-limiting for selected systems.

Sunitinib: from charge-density studies to interaction with proteins.

Protein kinases are targets for the treatment of a number of diseases. Sunitinib malate is a type I inhibitor of tyrosine kinases and was approved as a drug in 2006. This contribution constitutes the first comprehensive analysis of the crystal structures of sunitinib malate and of complexes of sunitinib with a series of protein kinases. The high-resolution single-crystal X-ray measurement and aspherical atom databank approach served as a basis for reconstruction of the charge-density distribution of sunitinib and its protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the sunitinib malate crystal structure to that in the protein binding pockets. Sunitinib forms nine preserved bond paths corresponding to hydrogen bonds and also to the C-H···O and C-H···π contacts common to the VEGRF2, CDK2, G2, KIT and IT kinases. In general, sunitinib interacts with the studied proteins with a similar electrostatic interaction energy and can adjust its conformation to fit the binding pocket in such a way as to enhance the electrostatic interactions, e.g. hydrogen bonds in ligand-kinase complexes. Such behaviour may be responsible for the broad spectrum of action of sunitinib as a kinase inhibitor.

Synthesis and crystallographic study of 1,25-dihydroxyergocalciferol analogs

The hybrid analogs of 1,25-dihydroxyergocalciferol (PRI-5201 and PRI-5202) were synthesized as potential anticancer agents using a convergent strategy. The analogs were designed by combining a 19-nor modification of the A-ring with the homologated and rigidified ergocalciferol-like side-chain of the previously obtained analogs PRI-1906 and PRI-1907. The strategy also allowed the novel efficient synthesis of 19-nor-1,25-dihydroxyergocalciferol (paricalcitol, PRI-5100) and its (24R)-diastereomer (PRI-5101). The single crystal X-ray structures of the 19-nor analogs (PRI-5100 and PRI-5101) were solved and refined. The A-ring of both analogs adopts exclusively chair β-conformation in the solid state. The side-chain of these analogs is coplanar with the CD-ring plane, while it is perpendicular in 1,25-dihydroxycholecalciferol.

Predicted structures of new Vitamin D Receptor agonists based on available X-ray structures.

Current efforts in the field of vitamin D are to develop 1,25(OH)2D3 analogs that exhibit equal or even increased anti-proliferative activity while possessing a reduced tendency to cause hypercalcemia. The study proposes a new, rational design of vitamin D analogs based on data available in the Protein Data Bank. Undertaken approach was to minimize the electrostatic interaction energies available after the reconstruction of charge density with the aid of the pseudoatom databank, namely the University at Buffalo Pseudoatom Databank (UBDB). Analysis of 24 vitamin D analogs, bearing similar molecular structures complexed with Vitamin D Receptor enabled the design of new agonists forming all advantageous interaction to the receptor, coded TB1, TB2, TB3 and TB4.

Synthesis and catalytic activity of ruthenium indenylidene complexes bearing unsymmetrical NHC containing a heteroaromatic moiety

New robust and air stable ruthenium(II) indenylidene second generation olefin metathesis catalysts with unsymmetrical N-heterocyclic carbene (NHC) ligands were synthesized. Model metathesis reactions were performed in the presence of newly-developed complexes in commercial grade toluene under air, leading to high conversions and good selectivities.

Crystal structure and tautomerism of capecitabine.

The crystal and molecular structure of capecitabine, an anticancer pharmaceutical substance, was solved and refined using single-crystal X-ray diffraction. The compound was synthesized from a derivative of cytidine by a modified method. The crystal of capecitabine for X-ray study was grown by seedless crystallization from a single solvent. The low and room temperature single-crystal X-ray crystallographic study revealed that capecitabine exists in the solid state exclusively in one of the two possible prototropic tautomers. In the molecular structure of this tautomer, the hydrogen atom is attached to the N3 nitrogen atom of the pyrimidine ring (imine tautomer) and not to the N(4) nitrogen of the carbamate (carbamate tautomer), as has been widely reported up to the present. The imine tautomer was also found to be thermodynamically preferred in the ab initio calculations. This finding indicates that the reported structural formula of capecitabine, as well as its systematic chemical name, must be revised.