Marko V. Rodić

Zn(II) complex with 2-quinolinecarboxaldehyde selenosemicarbazone: synthesis, structure, interaction studies with DNA/HSA, molecular docking and caspase-8 and -9 independent apoptose induction

A new Zn(II)-based potential chemotherapeutic agent was synthesized from the ligand 2-quinolinecarboxaldehyde selenosemicarbazone (Hqasesc). Single crystal X-ray diffraction analysis showed that the Zn(II) complex consists of a cation [Zn(Hqasesc)2]2+, two perchlorate anions and one ethanol solvent molecule. The interaction of calf thymus (CT) DNA and human serum albumin (HSA) with the Zn(II) complex was explored using absorption and emission spectral methods, and also has been supported by molecular docking studies. The complex has more affinity to minor DNA groove than major, with no significant intercalation. The HSA interaction studies of the complex revealed the quenching of the intrinsic fluorescence of the HSA through a static quenching mechanism. The antitumor activity of the ligand and the complex against pancreatic adenocarcinoma cell line (AsPC-1) and acute monocytic leukemia (THP-1) cells was evaluated. Both compounds are strong concentration-dependent apoptosis inducers in THP-1 cells. While Hqasesc in AsPC-1 cells induces apoptosis only at the highest concentration, treatment with the Zn complex shows a concentration-dependent apoptotic response, where the treated cells are arrested in the G1-to-S phase accompanied with extensive activation of caspase-8 and -9. These results indicate that the ligand and Zn(II) complex display cell phenotype specific activity.

Coordination compounds of a hydrazone derivative with Co(III), Ni(II), Cu(II) and Zn(II): Synthesis, characterization, reactivity assessment and biological evaluation

A new hydrazone-type ligand with a five N-donor set and its coordination compounds with Co(III), Ni(II), Cu(II) and Zn(II) metal centres were synthesized. The crystal and molecular structure of the Co(III) complex was determined by X-ray structural analysis. All the compounds were characterized by elemental analysis, molar conductivity and FT-IR spectral data. The cobalt(III) compound is a neutral binuclear complex formed by coordination of two, doubly deprotonated ligand anions as bridges between the Co(III) centres. The metal centres are additionally connected by a peroxido bridge, which was observed for the first time in Co(III) complexes with similar ligands. The other coordination compounds are mononuclear complexes wherein only one doubly deprotonated ligand is coordinated to the central ion in a tetradentate fashion. The structures were theoretically investigated employing density functional theory (DFT) calculations with B3LYP exchange–correlation functional and LACV3P+(d,p) basis sets for the coordination compounds and 6-31+G(d,p) basis set for the ligand. Molecular electrostatic potential (MEP) and average local ionization energy (ALIE) surfaces were calculated to study the reactive properties of the compounds. The thermal behaviour of the compounds was determined by simultaneous thermogravimetric-differential scanning calorimetric (TG-DSC) measurements and the results were correlated to the proposed structures and to calculated MEP/ALIE surfaces. The compounds were tested in vitro for antiproliferative effects on parental (L5178Y) mouse T-cell lymphoma cells, on L5178Y transfected with pHa ABCB1/A retrovirus and for reversal of multidrug resistance (MDR) in tumor cells by flow cytometry. The preliminary measurements showed that the cobalt(III) compound was an effective inhibitor of the ABC transporter PGP drug efflux pump. The ligand was somewhat less effective, the zinc complex had a moderate inhibition activity, whereas the nickel(II) and copper(II) compounds were inactive.

Crystal structure, thermal behavior, and microbiological activity of a thiosemicarbazide-type ligand and its cobalt complexes

The synthesis of a potentially bioactive mixed-valence CoIII/CoII complex with 2-acetylpyridine S-methylisothiosemicarbazone (HL) ligand is described. The crystal and molecular structure of the formed [CoIIIL2][CoIICl3py]·Me2CO (I) compound (py stands for pyridine) is determined by single-crystal X-ray crystallography. It’s thermal decomposition along with the decomposition of the ligand and six structurally related complexes with formulas [CoL2]NO3·MeOH (1), [CoL2]Br·MeOH (2), [CoL2]HSO4·MeOH (3), [CoL2]2[CoII(NCS)4] (4), [Co(HL)(L)]I2·2MeOH (5), and [Co(HL)(L)][CoIICl4]·MeOH (6) was determined by simultaneous TG/DSC measurements. The decomposition pattern is evaluated using TG/DTA-MS data. The results were related to the solvent/moisture content and the decomposition mechanism of the compounds. The antimicrobial activity of the ligand and of all the complexes was tested in vitro for selected gram-negative and gram-positive bacteria and fungi. The activity of the ligand against all tested bacteria is comparable with those obtained for standard antibiotics, while it is less active against fungi. Surprisingly, the activity of the complexes is very low. The low antimicrobial activity of the complexes may be in connection with their high thermodynamic and kinetic inertness in solution. The results are also supported by the relatively high thermal stability of the complexes.

Syntheses, crystal structures, and electrochemical characterizations of two octahedral iron(III) complexes with Schiff base of pyridoxal and aminoguanidine

This article presents the synthesis, physico-chemical, in particular voltammetric, characteristics of two iron(III) complexes with pyridoxal aminoguanidine (PLAG), [Fe(PLAG)Cl2(H2O)]Cl (1) and [Fe(PLAG)2](NO3)3 (2). As expected, the zwitterion of the chelate ligand is coordinated tridentate through oxygen of phenol and nitrogen atoms of azomethine and imino groups of the aminoguanidine fragment. In both complexes, Fe(III) is distorted octahedral. [Fe(PLAG)2](NO3)3 (2) is the first bis(ligand) complex with this ligand. Cyclic voltammetric characteristics of the ligand and complexes were studied in DMF in the presence of TBAP or LiCl as supporting electrolytes. The complexes are unstable in this solvent, especially in the presence of an excess of chloride, thus forming several reducible species whose stabilities and behaviors were characterized.

Synthesis, characterization and thermal behavior of copper(II) complexes with pyridoxal thiosemi (PLTSC)- and S-methylisothiosemicarbazone (PLITSC)

The syntheses of complexes of Cu(II) with biological active ligand, pyridoxal thiosemicarbazone (PLTSC) and its derivative, pyridoxal S-methylisothiosemicarbazone, are described. All coordination compounds were characterized by elemental analysis, molar conductivity and infrared spectra. The crystal and molecular structure of complexes [{Cu(μ-PLTSC)(H2O)}2](SO4)2·6H2O (2) and [{Cu(μ-PLTSC)(H2O)}2](SO4)2·2H2O (2a) is determined by single-crystal X-ray crystallography, too. The thermal decomposition of all the ligands and complexes was determined by simultaneous TG/DSC measurements. The decomposition mechanisms were compared and analyzed from the aspects of the relationships between the structures of the compounds and their thermal decomposition pattern.

Co(III) complex with (E)-2-(2-(pyridine-2-ylmethylene)hydrazinyl)-4-(4-tolyl)-1,3-thiazole: structure and activity against 2-D and 3-D cancer cell models

Abstract Co(III) complex with a 2-hydrazonylthiazole ligand was synthesized and characterized by single-crystal X-ray diffraction. In the inner sphere of the complex, two monoionic ligands are coordinated tridentately forming octahedral geometry around Co(III). Activity of the complex was investigated on MCF-7 breast cancer cell line, with cisplatin (CDDP) as a reference compound. Results showed that after 24-h incubation, Co(III) complex revealed stronger cytotoxic activity compared to CDDP. Treatment of MCF-7 3-D cell model with the complex at 10 μM concentration achieved complete suppression of spheroid growth in almost the same extent as at 100 μM. In combination treatments on MCF-7 spheroids, the complex acted synergistically with CDDP, while additive interaction type was achieved when the complex was applied together with paclitaxel.

Synthesis of endoperoxides by domino reactions of ketones and molecular oxygen

Domino reactions of ketones with molecular oxygen in the presence of potassium hydroxide and potassium t-butoxide afford cyclic hydroperoxy acetals (3,5-dihydroxy-1,2-dioxanes). Mixed endoperoxides can also be obtained in a three-component reaction of two ketones and oxygen.

Synthesis, characterization and in vitro cytotoxic activities of new steroidal thiosemicarbazones and thiadiazolines

A series of new steroidal mono- and bis(thiosemicarbazones) (2a–e and 3a–e) and corresponding mono- and bis(1,3,4-thiadiazolines) (4a–e and 5a–e) was synthesized, characterized and evaluated for their anticancer activity. Detailed NMR analysis of the mono- and bis(thiosemicarbazones) revealed the presence of two stereoisomers (Z and E) with different configurations in the hydrazone moiety at the C-3 position, where the substituents on the C(3)N double bond in the main isomers adopted the E configuration. The configurations at C-3 and C-17 in thiadiazolines 4a–e and 5a–e were deduced by detailed NMR analysis as well as by the examination of Dreiding molecular models and X-ray analysis of 3-thiadiazoline 4a, which confirmed the structure and absolute configuration at C-3. The synthesized compounds were tested against six cancer cell lines (HeLa, K562, MDA-MB-361, MDA-MB-453, LS174 and A549), the normal human cell line MRC-5 and peripheral blood mononuclear cells (PBMC) isolated from healthy donors. The best activity was exhibited by 3-thiosemicarbazones 2a, 2b, 2c and 2e and 3,17-bis(thiadiazolines) 5a and 5d. Examination of the mechanisms of cytotoxicity on cervical adenocarcinoma HeLa cells revealed the pro-apoptotic action of these compounds, which triggered both extrinsic and intrinsic apoptotic pathways. These compounds also showed the ability to decrease angiogenesis in vitro. In addition, 3,17-bis(thiadiazolines) 5a and 5d showed high selectivity in anticancer activity against all the examined malignant cell lines. Compound 5a displayed prominent anticancer potential. The tested compounds showed poor antimicrobial activity.

Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies

A series of 18 novel N‐Mannich bases derived from 5‐adamantyl‐1,2,4‐triazole‐3‐thione was synthesized and characterized using NMR spectroscopy and X‐ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL‐60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC‐5 compared to cancer cells. The effects of compounds 5b, 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase‐dependent apoptosis, while the anti‐angiogenic effects of 5b, 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.

Synthesis, crystal structure and local anti-inflammatory activity of the L-phenylalanine methyl ester derivative of dexamethasone-derived cortienic acid

The L-phenylalanine methyl ester derivative of dexamethasone- derived cortienic acid (DF) was synthesized and its crystal structure charac- terized by the X-ray diffraction method. The crystal system is orthorhombic with space group P212121 and cell constants a = 8.2969(3) A, b = 18.9358(8) A, c = 20.0904(6) A, V = 3156.4(2) A 3 and Z = 4. Ring A of the steroid nucleus and phenyl ring in the 17β-side chain are almost planar. Rings B and C have a slightly distorted chair conformation, whereas ring D has an envelope con- formation. The packing of DF is characterized by a network of intermolecular hydrogen bonds involving the O4 atom from one side of the steroid nucleus and O1 and F1 atoms from the other side as hydrogen bond acceptors. Apart from the intermolecular hydrogen bonds in the crystal packing, there are also numerous intramolecular hydrogen bonds of the N-H … O, C-H … O and C-H … F type. The local anti-inflammatory activity of DF was evaluated using