Sonja Grubišić

Conformational analysis of octa- and tetrahalogenated tetraphenylporphyrins and their metal derivatives

Abstract A new maximally diagonal force field for molecular modelling of metalloporphyrins is developed and optimized on the crystal structures of nickel(II) porphine, nickel(II) mono- tert -butylporphyrin and nickel(II) di- tert -butylporphyrin. It is then used to investigate non-planar distortions of octa- and tetrachloro tetraphenylporphyrins (TPP) and their Ni(II) and Tb(III) complexes. Molecular mechanics (MM) calculations reproduced very well the structure of Tb(III) octachloro-TPP (so far the only example of a crystallographically characterized chloro TPP metal derivative). Normal-coordinate structural decomposition (NSD) analysis was performed on the equilibrium structures obtained by MM calculations. As expected, sad distortion dominates in octachloro structures irrespective of the presence or the size of the central metal atom; dom distortion dominates in tetrachloro structures with large Tb(III) central atom, while sad , ruf , wav and pro distortions are present in various amounts in other tetrachloro structures (TPP free base and Ni(II) complex) depending on the pattern of peripheral chloro substitution on the pyrrole rings. Other observed regularities are: reduction of the conformational flexibility of the porphyrin core upon metallation, and increase of the dihedral angle between the phenyl groups and the mean LSQ plane of the porphyrin core, as well as the overall increase in structural regularity upon the increase of the size of the central metal atom.

Palladium(II) complexes with N-heteroaromatic bidentate hydrazone ligands: the effect of the chelate ring size and lipophilicity on in vitro cytotoxic activity.

Novel Pd(II) complex with N‐heteroaromatic Schiff base ligand, derived from 8‐quinolinecarboxaldehyde (q8a) and ethyl hydrazinoacetate (haOEt), was synthesized and characterized by analytical and spectroscopy methods. The structure of novel complex, as well as structures of its quinoline and pyridine analogues, was optimized by density functional theory calculations, and theoretical data show good agreement with experimental results. A cytotoxic action of the complexes was evaluated on cultures of human promyelocytic leukemia (HL‐60), human glioma (U251), rat glioma (C6), and mouse fibrosarcoma (L929) cell lines. Among investigated compounds, only complexes with quinoline‐based ligands reduce the cell numbers in a dose‐dependent manner in investigated cell lines. The observed cytotoxic effect of two isomeric quinoline‐based complexes is predominantly mediated through the induction of apoptotic cell death in HL‐60 cell line. The cytotoxicity of most efficient novel Pd(II) complex is comparable to the activity of cisplatin, in all cell lines investigated.

Structural characterization of the trans-equatorial isomer of (aqua)(ethylenediamine-N,N,N′-tripropionato)chromium(III) trihydrate,[Cr(edtrp)(H2O)] · 3H2O

The structure of trans-equatorial [Cr(edtrp)(H2O)] · 3H2O (edtrp3− is the anion of ethylenediamine-N,N,N′-tripropionic acid) was determined by single crystal X-ray diffraction. The chromium(III) ion is surrounded octahedrally by the two nitrogen and three oxygen atoms of the quinquedentate edtrp3−, forming a five-membered diamine ring and the three six-membered β-propionato chelate rings. The remaining coordination position is occupied by the H2O ligand. The crystal structure conformation is compared to the result of recent molecular mechanics analysis. The ring strain of R and G chelate rings was found to be in agreement with the previously proposed mechanisms for the C—N bond cleavage and recombination.

Structural analysis of conformational flexibility in (aqua)(propanediamine- N , N ′-diacetato- N -propionato)chromium(III) dihydrate. Crystal structure of cis -polar, trans (H2O,O5)-[Cr(1,3-pddap)(H2O)]·2H2O

The quinquedentate complex trans(H2O,O5)-[Cr(1,3-pddap)(H2O)] · 2H2O (where 1,3-pddap is the 1,3-propanediamine-N,N ′-diacetate-N-3-propionate ion) was prepared and its structure established by X-ray diffraction method. It crystallizes in the orthorhombic space group Pna21, a = 17.290(2), b = 10.821(2), c = 7.872(1) Å, Z = 4. The metal atom is surrounded octahedrally with two nitrogen and three oxygen donors of (1,3-pddap)3−, forming two six-membered and two five-membered metal chelate rings, and with one water molecule occupying the trans position with respect to the oxygen of the axial glycinate ring. Conformational analysis of the five geometrical isomers of [Cr(1,3-pddap)(H2O)], performed with the Consistent Force Field (CFF) program and recently developed edta force field, revealed that the global minimum is indeed the trans(H2O,O5) isomer with the geometry in a very good agreement with the crystallographic structure. General patterns for the conformational preferences of edta-type complexes of trivalent first-row transition metals are exposed and discussed.

Synthesis, characterization, DFT calculations and antimicrobial activity of Cd(II) complexes with the condensation product of 2-quinolinecarboxaldehyde and Girard’s T reagent

Abstract The chloro (1) and isocyanato (2) Cd(II) complexes with the condensation product of 2-quinolinecarboxaldehyde and trimethylammonium acetohydrazide chloride (Girard’s T reagent) (HLCl) have been synthesized and characterized by elemental analysis, IR, and NMR spectroscopy. The crystal structure of chloro Cd(II) complex (1) was determined. In 1 and 2, coordination surrounding of Cd(II) consists of deprotonated hydrazone ligand coordinated through NNO-donor atoms and two monodentates at the rest of the coordination places. Quantum chemical calculations of the molecular structures and the relative stabilities of linkage isomers of the Cd(II) complex showed that the isomer with N–Cd–N coordination of OCN− is the most stable. The investigated Cd(II) complexes showed lower activity than standard antimicrobial drugs.

Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and In-silico Studies

The novel approach in the treatment of complex multifactorial diseases, such as neurodegenerative disorders and cancer, requires a development of efficient multi-targeting oriented drugs. Since oxidative stress significantly contributes to the pathogenesis of cancer and neurodegenerative disorders, potential drug candidates should possess good antioxidant properties. Due to promising biological activities shown for structurally related (1,3-thiazol-2-yl)hydrazones, a focused library of 12 structurally related benzylidene-based (1,3-selenazol-2-yl)hydrazones was designed as potential multi-targeting compounds. Monoamine oxidases (MAO) A/B inhibition properties of this class of compounds have been investigated. Surprisingly, the p-nitrophenyl-substituted (1,3-selenazol-2-yl)hydrazone 4 showed MAO B inhibition in a nanomolar concentration range (IC50 = 73 nM). Excellent antioxidant properties were confirmed in a number of different in vitro assays. Antiproliferative activity screening on a panel of six human solid tumor cell lines showed that potencies of some of the investigated compounds was comparable or even better than that of the positive control 5-fluorouracil. In-silico calculations of ADME properties pointed to promising good pharmacokinetic profiles of investigated compounds. Docking studies suggest that some compounds, compared to positive controls, have the ability to strongly interact with targets relevant to cancer such as 5′-nucleotidase, and to neurodegenerative diseases such as the small conductance calcium-activated potassium channel protein 1, in addition to confirmation of inhibitory binding at MAO B.

Assessing the dispersive and electrostatic components of the selenium–aromatic interaction energy by DFT

Selenium has been increasingly recognized as an important element in biological systems, which participates in numerous biochemical processes in organisms, notably in enzyme reactions. Selenium can substitute sulfur of cysteine and methionine to form their selenium analogues, selenocysteine (Sec) and selenomethionine (SeM). The nature of amino acid pockets in proteins is dependent on their composition and thus different non-covalent forces determine the interactions between selenium of Sec or SeM and other functional groups, resulting in specific biophysical behavior. The discrimination of selenium toward sulfur has been reported. In order to elucidate the difference between the nature of S-π and Se-π interactions, we performed extensive DFT calculations of dispersive and electrostatic contributions of Se-π interactions in substituted benzenes/hydrogen selenide (H2Se) complexes. The results are compared with our earlier reported S-π calculations, as well as with available experimental data. Our results show a larger contribution of dispersive interactions in Se-π systems than in S-π ones, which mainly originate from the attraction between Se and substituent groups. We found that selenium exhibits a strong interaction with aromatic systems and may thus play a significant role in stabilizing protein folds and protein–inhibitor complexes. Our findings can also provide molecular insights for understanding enzymatic specificity discrimination between single selenium versus a sulfur atom, notwithstanding their very similar chemical properties.