Marija Ristić | University of Kragujevac, Serbia (original) (raw)
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Papers by Marija Ristić
Springer, 2024
In order to discover a new antibiotic drug with better or similar activity of the already existin... more In order to discover a new antibiotic drug with better or similar activity of the already existing drugs, a series of novel cobalt(II) complexes with β-diketonate as ligands is synthesized and tested on four strains of bacteria and four species of fungi. All compounds showed notable antimicrobial activity against all tested strains. More importantly, some cobalt(II) complexes displayed greater activity than ketoconazole. It is important to notice that on the tested strains Mucor mucedo and Penicillium italicum complex 2B showed five times better activity compared to ketoconazole, while complex 2D had two times better activity on Penicillium italicum strain compared to ketoconazole. Moreover, investigations with bovine serum albumin were performed. Investigations showed that the tested complexes have an appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of the tested cobalt(II) complexes with β-diketonate as ligands to bovine serum albumin, tyrosyl-tRNA synthetase, topoisomerase II DNA gyrase, and cytochrome P450 14 alpha-sterol demethylase. In conclusion, all the results indicated the great prospective of the novel cobalt complexes for some potential clinical applications in the future.
Acta Horticulturae et Regiotecturae
Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family.... more Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family. The species of this genus are consumed worldwide as fresh or in form of beverages. They include well-known crops lemons, oranges, mandarins, grapefruits, and limes. The industrial processing of these fruits produces high amounts of waste (around 50%) which is a valuable source of essential oils. Since they are produced mainly from peel, considered waste, these essential oils have great economic value. In that regard, the aim of this study was to evaluate the chemical composition of the essential oil obtained from the peel of Citrus aurantium amara, as well as to assess the biological effects by the means of antioxidant and antibacterial activity. Results of GC and GC/MS analysis characterized this EO as a valuable source of limonene found in the amount of 90.4% of the total. Results of antioxidant activity indicate better inhibition of ABTS•+ (44.93 ±1.45%) compared to the DPPH• (11.03 ...
Dalton transaction, 2024
Four neutral Rh1–Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimid... more Four neutral Rh1–Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants Kb are moderately strong (∼104 M−1), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2–Rh4 complexes exerted a strong inhibitory effect on G+ bacteria B. cereus and G− bacteria V. parahaemolyticus as well as on the yeast C. tropicalis, which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1–Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1–Rh4 complexes inhibit cell proliferation via different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells).
RSC Advances, 2017
Two rhodium(III) complexes [Rh(ed3a)(OH 2)]$H 2 O (1) and Na[Rh(ed3a)Cl]$H 2 O (2) with ethylened... more Two rhodium(III) complexes [Rh(ed3a)(OH 2)]$H 2 O (1) and Na[Rh(ed3a)Cl]$H 2 O (2) with ethylenediamine-N,N,N 0-triacetate (ed3a) have been synthesized and characterized by elemental, spectroscopic and structural analyses. The crystal structure of (1) and (2) and the spectroscopic analysis of the two rhodium(III)-ed3a complexes are discussed in detail. The protonation constants of H 3 ed3a and the conditional stability constants of its Rh III complexes have been determined in aqueous solution by pH potentiometry and UV-Vis spectrophotometry. Molecular mechanics (MM) and density functional theory (DFT) have been used to model all possible geometric isomers, determine the global energy minimum and compare the computed with the experimentally observed structures. The cytotoxic activity of the new Rh III complexes was evaluated by an MTT assay against four human cancer lines (MCF-7, A549, HT-29 and HeLa) and a normal human cell line (MRC-5). A549, HT-29 and HeLa cells were sensitive to all compounds tested, while the breast carcinoma cell line MCF-7 was only sensitive to the reference compounds (doxorubicin and cisplatin). Western blot (WB) analysis of the effects of the tested compounds indicates that both complexes increase the expression of caspase 3 and consequently the involvement of this enzyme in apoptotic processes of the treated cells. WB also demonstrates proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP) in HeLa cells after treatment with both tested substances. Flow cytometry confirmed apoptotic cell death and showed the induction of cell cycle termination as a possible promoter of apoptosis.
![Research paper thumbnail of Synthesis, characterization, HSA/DNA interactions and antitumor activity of new [Ru(η6-p-cymene)Cl2(L)] complexes](https://attachments.academia-assets.com/111552583/thumbnails/1.jpg)
](Journal of Inorganic Biochemistry, 2020
Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands... more Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands 5-(methylamino)-3-pyrrolidine-1-ylisothiazole-4-carbonitrile (1), 5-(methylamino)-3-(4-methylpiperazine-1-yl)isothiazole-4-carbonitrile (2) and 5-(methylamino)-3-morpholine-4-ylisothiazole-4-carbonitrile (3): [Ru(η 6-pcymene)Cl 2 (L1)]•H 2 O (4), [Ru(η 6-p-cymene)Cl 2 (L2)] (5) and [Ru(η 6-p-cymene)Cl 2 (L3)] (6). All complexes were characterized by IR, UV-Vis, NMR spectroscopy, and elemental analysis. The molecular structures of all ligands and complexes 4 and 6 were determined by an X-ray. The results of the interactions of CT-DNA (calf thymus deoxyribonucleic acid) and HSA (human serum albumin) with ruthenium (II) complexes reveal that complex 4 binds well to CT-DNA and HSA. Kinetic and thermodynamic parameters for the reaction between complex and HSA confirmed the associative mode of interaction. The results of Quantum mechanics (QM) modelling and docking experiments toward DNA dodecamer and HSA support the strongest binding of the complex 4 to DNA major groove, as well as its binding to IIa domain of HSA with the lowest ΔG energy, which agrees with the solution studies. The modified GOLD docking results are indicative for Ru(p-cymene)LCl••(HSA••GLU292) binding and GOLD/MOPAC(QM) docking/modelling of DNA/Ligand (Ru(II)-N(7)dG7) covalent binding. The cytotoxic activity of compounds was evaluated by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Neither of the tested compounds shows activity against a healthy MRC-5 cell line while the MCF-7 cell line is the most sensitive to all. Compounds 3, 4 and 5 were about two times more active than cisplatin, while the antiproliferative activity of 6 was almost the same as with cisplatin. Flow cytometry analysis showed the apoptotic death of the cells with a cell cycle arrest in the subG1 phase.
Inorganica chimica acta, 2018
Two piano-stool ruthenium(II) complexes [Ru(η 6-p-cymene)(N-MeIm) 3 ]Cl 2 •2H 2 O (1) and [Ru(η 6... more Two piano-stool ruthenium(II) complexes [Ru(η 6-p-cymene)(N-MeIm) 3 ]Cl 2 •2H 2 O (1) and [Ru(η 6-p-cymene)(N-PrIm)Cl 2 ] (2) respectively have been synthesized and characterized by elemental, spectral and structural analysis. Crystal structures of (1) and (2) have been verified by X-ray diffraction analysis. Docking experiments toward DNA dodecamer have been done. Good ΔG binding values of the complexes with imidazole derivatives comparable with ethylene-diamine complex indicate a high potential of these compounds in the formation of DNA lesions and therefore their good cytotoxic status. The interaction of CT-DNA with ruthenium(II) complexes has been studied by means of absorption and fluorescence measurements. The binding constant, K b and the Stern-Volmer quenching constant reveal that complex (2) binds well to CT-DNA. The cytotoxic activity of Ru(II) complexes with N-RIm (R = methyl or propyl) were evaluated by MTT assay. A-549, HT-29 and HeLa cells were sensitive to all compounds tested, while the breast carcinoma cell line MCF-7 was resistant only to the complex (1). Flow cytometric analysis and fluorescent microscopy showed that ruthenium(II) complexes in HeLa cells induce apoptosis and G0/G1 cell cycle arrest and almost completely inhibit DNA synthesis. Western blot also demonstrated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP) in HeLa cells after treatment with both tested substances.
Inorganica chimica acta, 2019
The trans(O 6) isomer (trans(O 6) refer to two six-membered rings in trans position) of the [Ba(H... more The trans(O 6) isomer (trans(O 6) refer to two six-membered rings in trans position) of the [Ba(H 2 O) 4 ][Ni(1,3pddadp)]•4H 2 O (1,3-pddadp = 1,3-propanediamine-N,N′-diacetate-N,N′-di-3-propionate) was synthesized and spectroscopically characterized (IR, UV-Vis). The trans(O 6) geometry was confirmed by X-ray diffraction analysis. Single crystal X-ray diffraction of the complex revealed an octahedral geometry around the Ni(II) centre. Extensive strain analysis of [M(edta-type)] 2− complexes (M = Ni, Co, Cu) has been performed and discussed in detail. DFT/NBO analysis (DFT = Density Functional Theory, NBO = Natural Bond Orbital) was performed for all isomers of [Ni(1,3-pddadp)] 2− complex. DFT theory shows that trans(O 6) isomer is 0.53 kcal mol −1 more stable than trans(O 5 O 6) and 1.95 kcal mol −1 more stable than trans(O 5). NBO analysis for all three isomers predicts the existence of a 3-center 2-electron (β system) A:-Ni-: B hyperbonds along with O:-C-:O carboxylate triads. The Second-Order Perturbation Theory Analysis predicts molecular stabilization that comes from delocalization caused by n A → σ NiB* or n B → σ NiA* charge transfer.
Polyhedron, 2019
The trans(O 5 O 6) isomer of the Na[Rh(eddadp)]Á4H 2 O and the K[Co(eddadp)]Á3H 2 O (eddadp = eth... more The trans(O 5 O 6) isomer of the Na[Rh(eddadp)]Á4H 2 O and the K[Co(eddadp)]Á3H 2 O (eddadp = ethylenediamine-N,N 0-diacetate-N,N 0-di-3-propionate) were synthesized and Na[Rh(eddadp)]Á4H 2 O structure was confirmed by X-ray diffraction analysis. The percentage of particular isomers found in reaction equilibrium mixtures of [M(eddadp)] À complex has been reported. Single crystal X-ray diffraction of the complex revealed an octahedral geometry of the Rh(III) centre. Improved structural distortion analysis of M(III) (M = Rh, Co) complexes with symmetric edta-type of ligands containing mixed carboxylate and diamine rings was made. Structural distortion analysis has determined high values of total deviation of the octahedral angles (D(O h)) for both existing trans(O 5) (34°) and trans(O 5 O 6) (41°) isomers of [Rh (eddadp)] À complex, while in the case of a similar Co(III) complex, relatively low value (31°) for trans (O 5) has been established. Extensive QM/NBO calculations were made for both systems [M(eddadp)] À and [M(1,3-pddadp)] À using different DFT methods (B3LYP/SDD, M06/SDD, MP2/SDD). By correlating the structural parameters obtained from X-ray and DFT optimized 3D structures, the B3LYP/SDD method was used as the method of choice. Based on the correlation between the energies of the optimized systems and the strain parameters, the existence of the trans(O 6) isomer of the [Rh(1,3-pddadp)] À complex was predicted. NRT (Natural Resonance Theory) analysis gave the best resonances for each isomer. Here the stability of particular isomer has been described in terms of 3-CHB bonds involving metal ions and Second Order Perturbation Theory analysis using Donor/Acceptor energies. Further, to explain the bonding nature of M-edta-type complexes the Natural Coulomb Electrostatics (NCE) analysis has been done as well. The pairwise steric exchange interaction E I,J pwx results obtained for the best-ranked resonances of different isomers are in excellent agreement with favored isomers reported so far. For the energy limit of the possibility of forming geometric isomers, a value of about 6 kcal mol À1 is proposed.
Polyhedron, 2018
Two new octahedral Rh(III) complexes that are potential chemotherapeutic agents have been synthes... more Two new octahedral Rh(III) complexes that are potential chemotherapeutic agents have been synthesized from the 1,3-propanediamine-N,N,N'-triacetate ligand (1,3-pd3a): [Rh(1,3-pd3a)(H 2 O)]Á2H 2 O (1) and Na [Rh(1,3-pd3a)Cl]Á2H 2 O (2). Both complexes were characterized by IR, UV-Vis and NMR spectroscopy, as well as elemental analysis. Only the structure of 2 was determined by a single crystal X-ray diffraction study. The asymmetric unit contains the negatively charged rhodium complex, a sodium ion and two water molecules. The positions of the carboxylate groups define the cis-polar geometry. DFT calculations on 1 and 2 have also been done to confirm experimental results. In order to determine the protonation constants of 1,3-H 3 pd3a, stability constants and the stoichiometry of the complexes in aqueous solution, pH-potentiometry and UV-Vis spectrophotometry were used. Docking of 1 to human serum albumin (HSA) gives the reasonable assumption that this complex can be easily transported to the target cells. The complexes, as well as the 1,3-pd3a and ed3a ligands, were tested against various cancer and one normal human cell lines. Complex 2 and both ligands display significant cytotoxicity against the HeLa cancer cell line, while 1 shows good antitumor activity against MCF-7. Flow cytometry analysis showed the apoptotic death of the cells with cell cycle arrest in the G2/M phase (Na[Rh(1,3-pd3a)Cl]Á2H 2 O) and G0/G1 phase (1,3-pd3a).
![Research paper thumbnail of Preparation, configurational and DFT-NBO analysis of nickel(II) complexes with edta-type ligands containing six-membered backbone ring: crystal structure of [Ni(H 2 O) 6 ][Ni(1,3-pdta)]•2H 2 O](https://attachments.academia-assets.com/111551119/thumbnails/1.jpg)
](Journal of coordination chemistry, 2013
New hexadentate nickel(II) complex Mg[Ni(1,3-pd3ap)]·10H2O containing unsymmetrical edta-type lig... more New hexadentate nickel(II) complex Mg[Ni(1,3-pd3ap)]·10H2O containing unsymmetrical edta-type ligand, 1,3-propanediamine-N,N,N′-triacetate-N′-3-propionate (1,3-pd3ap), has been prepared, chromatographically separated, and characterized. Only one [trans(O5)] of the two possible geometrical isomers was isolated. In this isomer, the two five-membered glycinate rings (R rings) occupy
trans-axial sites while the one glycinate ring and one β-alaninate ring lie in the equatorial plane
with the two diamine nitrogens (G rings). This result confirms the assignment made on the basis of
the density functional theory (DFT), IR, and UV–Vis spectral data analysis. In order to see cation
influence on the structural and electronic behavior, [Ni(H2O)6][Ni(1,3-pdta)]·2H2O complex has also been prepared and its structure verified by an X-ray analysis. Spectral data and electronic
transition assignment, DFT–natural bonding orbital, and an extensive strain analysis are discussed in comparison with those of other [Ni(edta-type)]2 complexes of known configuration.
Polyhedron, 2013
A new hexadentate chromium(III) complex, Na[Cr(l,3-pd3ap)]Á3H 2 O, containing an unsymmetrical ed... more A new hexadentate chromium(III) complex, Na[Cr(l,3-pd3ap)]Á3H 2 O, containing an unsymmetrical edta-type ligand, the 1,3-propanediam ine-N,N,N 0-triacetate-N 0-3-propionate ion (1,3-pd3ap), has been prepared, chromatographically separated and characterized. Only one [trans(O 5)] of the two possible geometrical isomers was isolated. In this isomer the two five-membered glycinate rings (R rings) occupy trans-axial sites, while the one glycinate ring and one b-alaninate ring lie in the equatorial plane wit h the two diamine nitrogens (G rings). This result confirms the assignment made on the basis of Density Functional Theory (DFT), IR and UV-Vis spectral data analyses. The spectral data and electron ic transition assignment, DFT-NBO, Ligand Field DFT and extensive strain analysis are discussed by a comparison with those of other [Cr(edta-type)] À complexes of known configurations. The stoichiometry and stability of the complexes formed between the chromiu m(III) ion and 1,3-propanediamine-N,N,N 0-triacetic-N 0-propionic acid (H 4 1,3-pd3ap) were determine d in aqueous solution by potentiometry at 25 °C and 0.1 M NaCl ionic strength. The existence of Cr(H n L), n = 0, 1, 2 and 3 type complexes were verified. The formation of the Cr(OH)L comp lex was observed at higher pH values. The concentration distribution diagra ms of the complexes were evaluated.
Chemistry select, 2020
Two new neutral ruthenium(II) complexes [Ru(η6-p-cymene) Cl2(1)] (3) and [Ru(η6-p-cymene)Cl2(2)]... more Two new neutral ruthenium(II) complexes [Ru(η6-p-cymene)
Cl2(1)] (3) and [Ru(η6-p-cymene)Cl2(2)] (4) (1=5-(phenylamino)-
3-pyrrolidin-1-ylisothiazole-4-carbonitrile; 2=3-morpholin-4-yl-
5-(phenylamino)isothiazole-4-carbonitrile) have been synthesized
and characterized using elemental analysis, IR, UV-Vis and
NMR spectroscopy. The crystal structure was confirmed for
complex 3 and both ligands. Examination of the interactions of
ligands and complexes with CT-DNA (Calf Thymus DNA), as
well as with HSA (Human Serum Albumin) revealed that ligands
and complexes could interact with CT-DNA through intercalation
and could bind strongly with HSA. Docking experiments
toward DNA dodecamer indicate excellent accordance with
experimental ΔG values. The cytotoxic activity of ligands and
complexes was evaluated by MTT assay against HCT116 and
HeLa tumoral cells. The complexes 3 and 4 showed good
activity and selectivity on HCT116 cells. Neither of the tested
compounds shows cytotoxic activity against a healthy MRC-
5 cell line. Flow cytometry analysis showed the apoptotic death
of the HCT116 cells with a cell cycle arrest in the S-phase.
Acta Horticulturae et Regiotecturae, May 23, 2023
Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family.... more Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family. The species of this genus are
consumed worldwide as fresh or in form of beverages. They include well-known crops lemons, oranges, mandarins, grapefruits,
and limes. The industrial processing of these fruits produces high amounts of waste (around 50%) which is a valuable source
of essential oils. Since they are produced mainly from peel, considered waste, these essential oils have great economic value.
In that regard, the aim of this study was to evaluate the chemical composition of the essential oil obtained from the peel of
Citrus aurantium amara, as well as to assess the biological eff ects by the means of antioxidant and antibacterial activity. Results
of GC and GC/MS analysis characterized this EO as a valuable source of limonene found in the amount of 90.4% of the total.
Results of antioxidant activity indicate better inhibition of ABTS•+ (44.93 ±1.45%) compared to the DPPH• (11.03 ±1.08%). Moreover,
the results of the antimicrobial assessment using the disc diff usion method displayed low inhibition potency of this essential oil
towards G+ and G- bacteria and yeast strains.
Journal of the Serbian Chemical Society, 2022
Only one (trans(O5)-Na[Rh(ED3AP)]?3H2O) of possible two isomers was synthesized and characterized... more Only one (trans(O5)-Na[Rh(ED3AP)]?3H2O) of possible two isomers was synthesized and characterized by single crystal X-ray analysis, IR and UV?Vis spectroscopy. Computational analysis of both isomers was performed with three levels of theory (B3LYP/TZV, BP86/TZV, OPBE/TZV), which gave consistent results. The more stable isomer by total energy and ligand field stabilization energy (LFSE) was trans(O5) which appeared in synthesis. The calculation of excited state energies complied with UV?Vis spectra, especially with OPBE functional. The results of excited state energy pointed out the differences among isomers in means of a splitting pattern of 1T2g excited state term. Both isomers have a strongly delocalized structure, according to the natural bonding orbital (NBO) analysis. NBO analysis shows that the trans(O5) isomer is more stable than trans(O5O6) for approx. 87 kJ/mol. Therefore, only the trans(O5) isomer is present in the reaction mixture.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Springer, 2024
In order to discover a new antibiotic drug with better or similar activity of the already existin... more In order to discover a new antibiotic drug with better or similar activity of the already existing drugs, a series of novel cobalt(II) complexes with β-diketonate as ligands is synthesized and tested on four strains of bacteria and four species of fungi. All compounds showed notable antimicrobial activity against all tested strains. More importantly, some cobalt(II) complexes displayed greater activity than ketoconazole. It is important to notice that on the tested strains Mucor mucedo and Penicillium italicum complex 2B showed five times better activity compared to ketoconazole, while complex 2D had two times better activity on Penicillium italicum strain compared to ketoconazole. Moreover, investigations with bovine serum albumin were performed. Investigations showed that the tested complexes have an appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of the tested cobalt(II) complexes with β-diketonate as ligands to bovine serum albumin, tyrosyl-tRNA synthetase, topoisomerase II DNA gyrase, and cytochrome P450 14 alpha-sterol demethylase. In conclusion, all the results indicated the great prospective of the novel cobalt complexes for some potential clinical applications in the future.
Acta Horticulturae et Regiotecturae
Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family.... more Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family. The species of this genus are consumed worldwide as fresh or in form of beverages. They include well-known crops lemons, oranges, mandarins, grapefruits, and limes. The industrial processing of these fruits produces high amounts of waste (around 50%) which is a valuable source of essential oils. Since they are produced mainly from peel, considered waste, these essential oils have great economic value. In that regard, the aim of this study was to evaluate the chemical composition of the essential oil obtained from the peel of Citrus aurantium amara, as well as to assess the biological effects by the means of antioxidant and antibacterial activity. Results of GC and GC/MS analysis characterized this EO as a valuable source of limonene found in the amount of 90.4% of the total. Results of antioxidant activity indicate better inhibition of ABTS•+ (44.93 ±1.45%) compared to the DPPH• (11.03 ...
Dalton transaction, 2024
Four neutral Rh1–Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimid... more Four neutral Rh1–Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants Kb are moderately strong (∼104 M−1), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2–Rh4 complexes exerted a strong inhibitory effect on G+ bacteria B. cereus and G− bacteria V. parahaemolyticus as well as on the yeast C. tropicalis, which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1–Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1–Rh4 complexes inhibit cell proliferation via different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells).
RSC Advances, 2017
Two rhodium(III) complexes [Rh(ed3a)(OH 2)]$H 2 O (1) and Na[Rh(ed3a)Cl]$H 2 O (2) with ethylened... more Two rhodium(III) complexes [Rh(ed3a)(OH 2)]$H 2 O (1) and Na[Rh(ed3a)Cl]$H 2 O (2) with ethylenediamine-N,N,N 0-triacetate (ed3a) have been synthesized and characterized by elemental, spectroscopic and structural analyses. The crystal structure of (1) and (2) and the spectroscopic analysis of the two rhodium(III)-ed3a complexes are discussed in detail. The protonation constants of H 3 ed3a and the conditional stability constants of its Rh III complexes have been determined in aqueous solution by pH potentiometry and UV-Vis spectrophotometry. Molecular mechanics (MM) and density functional theory (DFT) have been used to model all possible geometric isomers, determine the global energy minimum and compare the computed with the experimentally observed structures. The cytotoxic activity of the new Rh III complexes was evaluated by an MTT assay against four human cancer lines (MCF-7, A549, HT-29 and HeLa) and a normal human cell line (MRC-5). A549, HT-29 and HeLa cells were sensitive to all compounds tested, while the breast carcinoma cell line MCF-7 was only sensitive to the reference compounds (doxorubicin and cisplatin). Western blot (WB) analysis of the effects of the tested compounds indicates that both complexes increase the expression of caspase 3 and consequently the involvement of this enzyme in apoptotic processes of the treated cells. WB also demonstrates proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP) in HeLa cells after treatment with both tested substances. Flow cytometry confirmed apoptotic cell death and showed the induction of cell cycle termination as a possible promoter of apoptosis.
Journal of Inorganic Biochemistry, 2020
Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands... more Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands 5-(methylamino)-3-pyrrolidine-1-ylisothiazole-4-carbonitrile (1), 5-(methylamino)-3-(4-methylpiperazine-1-yl)isothiazole-4-carbonitrile (2) and 5-(methylamino)-3-morpholine-4-ylisothiazole-4-carbonitrile (3): [Ru(η 6-pcymene)Cl 2 (L1)]•H 2 O (4), [Ru(η 6-p-cymene)Cl 2 (L2)] (5) and [Ru(η 6-p-cymene)Cl 2 (L3)] (6). All complexes were characterized by IR, UV-Vis, NMR spectroscopy, and elemental analysis. The molecular structures of all ligands and complexes 4 and 6 were determined by an X-ray. The results of the interactions of CT-DNA (calf thymus deoxyribonucleic acid) and HSA (human serum albumin) with ruthenium (II) complexes reveal that complex 4 binds well to CT-DNA and HSA. Kinetic and thermodynamic parameters for the reaction between complex and HSA confirmed the associative mode of interaction. The results of Quantum mechanics (QM) modelling and docking experiments toward DNA dodecamer and HSA support the strongest binding of the complex 4 to DNA major groove, as well as its binding to IIa domain of HSA with the lowest ΔG energy, which agrees with the solution studies. The modified GOLD docking results are indicative for Ru(p-cymene)LCl••(HSA••GLU292) binding and GOLD/MOPAC(QM) docking/modelling of DNA/Ligand (Ru(II)-N(7)dG7) covalent binding. The cytotoxic activity of compounds was evaluated by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Neither of the tested compounds shows activity against a healthy MRC-5 cell line while the MCF-7 cell line is the most sensitive to all. Compounds 3, 4 and 5 were about two times more active than cisplatin, while the antiproliferative activity of 6 was almost the same as with cisplatin. Flow cytometry analysis showed the apoptotic death of the cells with a cell cycle arrest in the subG1 phase.
Inorganica chimica acta, 2018
Two piano-stool ruthenium(II) complexes [Ru(η 6-p-cymene)(N-MeIm) 3 ]Cl 2 •2H 2 O (1) and [Ru(η 6... more Two piano-stool ruthenium(II) complexes [Ru(η 6-p-cymene)(N-MeIm) 3 ]Cl 2 •2H 2 O (1) and [Ru(η 6-p-cymene)(N-PrIm)Cl 2 ] (2) respectively have been synthesized and characterized by elemental, spectral and structural analysis. Crystal structures of (1) and (2) have been verified by X-ray diffraction analysis. Docking experiments toward DNA dodecamer have been done. Good ΔG binding values of the complexes with imidazole derivatives comparable with ethylene-diamine complex indicate a high potential of these compounds in the formation of DNA lesions and therefore their good cytotoxic status. The interaction of CT-DNA with ruthenium(II) complexes has been studied by means of absorption and fluorescence measurements. The binding constant, K b and the Stern-Volmer quenching constant reveal that complex (2) binds well to CT-DNA. The cytotoxic activity of Ru(II) complexes with N-RIm (R = methyl or propyl) were evaluated by MTT assay. A-549, HT-29 and HeLa cells were sensitive to all compounds tested, while the breast carcinoma cell line MCF-7 was resistant only to the complex (1). Flow cytometric analysis and fluorescent microscopy showed that ruthenium(II) complexes in HeLa cells induce apoptosis and G0/G1 cell cycle arrest and almost completely inhibit DNA synthesis. Western blot also demonstrated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP) in HeLa cells after treatment with both tested substances.
Inorganica chimica acta, 2019
The trans(O 6) isomer (trans(O 6) refer to two six-membered rings in trans position) of the [Ba(H... more The trans(O 6) isomer (trans(O 6) refer to two six-membered rings in trans position) of the [Ba(H 2 O) 4 ][Ni(1,3pddadp)]•4H 2 O (1,3-pddadp = 1,3-propanediamine-N,N′-diacetate-N,N′-di-3-propionate) was synthesized and spectroscopically characterized (IR, UV-Vis). The trans(O 6) geometry was confirmed by X-ray diffraction analysis. Single crystal X-ray diffraction of the complex revealed an octahedral geometry around the Ni(II) centre. Extensive strain analysis of [M(edta-type)] 2− complexes (M = Ni, Co, Cu) has been performed and discussed in detail. DFT/NBO analysis (DFT = Density Functional Theory, NBO = Natural Bond Orbital) was performed for all isomers of [Ni(1,3-pddadp)] 2− complex. DFT theory shows that trans(O 6) isomer is 0.53 kcal mol −1 more stable than trans(O 5 O 6) and 1.95 kcal mol −1 more stable than trans(O 5). NBO analysis for all three isomers predicts the existence of a 3-center 2-electron (β system) A:-Ni-: B hyperbonds along with O:-C-:O carboxylate triads. The Second-Order Perturbation Theory Analysis predicts molecular stabilization that comes from delocalization caused by n A → σ NiB* or n B → σ NiA* charge transfer.
Polyhedron, 2019
The trans(O 5 O 6) isomer of the Na[Rh(eddadp)]Á4H 2 O and the K[Co(eddadp)]Á3H 2 O (eddadp = eth... more The trans(O 5 O 6) isomer of the Na[Rh(eddadp)]Á4H 2 O and the K[Co(eddadp)]Á3H 2 O (eddadp = ethylenediamine-N,N 0-diacetate-N,N 0-di-3-propionate) were synthesized and Na[Rh(eddadp)]Á4H 2 O structure was confirmed by X-ray diffraction analysis. The percentage of particular isomers found in reaction equilibrium mixtures of [M(eddadp)] À complex has been reported. Single crystal X-ray diffraction of the complex revealed an octahedral geometry of the Rh(III) centre. Improved structural distortion analysis of M(III) (M = Rh, Co) complexes with symmetric edta-type of ligands containing mixed carboxylate and diamine rings was made. Structural distortion analysis has determined high values of total deviation of the octahedral angles (D(O h)) for both existing trans(O 5) (34°) and trans(O 5 O 6) (41°) isomers of [Rh (eddadp)] À complex, while in the case of a similar Co(III) complex, relatively low value (31°) for trans (O 5) has been established. Extensive QM/NBO calculations were made for both systems [M(eddadp)] À and [M(1,3-pddadp)] À using different DFT methods (B3LYP/SDD, M06/SDD, MP2/SDD). By correlating the structural parameters obtained from X-ray and DFT optimized 3D structures, the B3LYP/SDD method was used as the method of choice. Based on the correlation between the energies of the optimized systems and the strain parameters, the existence of the trans(O 6) isomer of the [Rh(1,3-pddadp)] À complex was predicted. NRT (Natural Resonance Theory) analysis gave the best resonances for each isomer. Here the stability of particular isomer has been described in terms of 3-CHB bonds involving metal ions and Second Order Perturbation Theory analysis using Donor/Acceptor energies. Further, to explain the bonding nature of M-edta-type complexes the Natural Coulomb Electrostatics (NCE) analysis has been done as well. The pairwise steric exchange interaction E I,J pwx results obtained for the best-ranked resonances of different isomers are in excellent agreement with favored isomers reported so far. For the energy limit of the possibility of forming geometric isomers, a value of about 6 kcal mol À1 is proposed.
Polyhedron, 2018
Two new octahedral Rh(III) complexes that are potential chemotherapeutic agents have been synthes... more Two new octahedral Rh(III) complexes that are potential chemotherapeutic agents have been synthesized from the 1,3-propanediamine-N,N,N'-triacetate ligand (1,3-pd3a): [Rh(1,3-pd3a)(H 2 O)]Á2H 2 O (1) and Na [Rh(1,3-pd3a)Cl]Á2H 2 O (2). Both complexes were characterized by IR, UV-Vis and NMR spectroscopy, as well as elemental analysis. Only the structure of 2 was determined by a single crystal X-ray diffraction study. The asymmetric unit contains the negatively charged rhodium complex, a sodium ion and two water molecules. The positions of the carboxylate groups define the cis-polar geometry. DFT calculations on 1 and 2 have also been done to confirm experimental results. In order to determine the protonation constants of 1,3-H 3 pd3a, stability constants and the stoichiometry of the complexes in aqueous solution, pH-potentiometry and UV-Vis spectrophotometry were used. Docking of 1 to human serum albumin (HSA) gives the reasonable assumption that this complex can be easily transported to the target cells. The complexes, as well as the 1,3-pd3a and ed3a ligands, were tested against various cancer and one normal human cell lines. Complex 2 and both ligands display significant cytotoxicity against the HeLa cancer cell line, while 1 shows good antitumor activity against MCF-7. Flow cytometry analysis showed the apoptotic death of the cells with cell cycle arrest in the G2/M phase (Na[Rh(1,3-pd3a)Cl]Á2H 2 O) and G0/G1 phase (1,3-pd3a).
Journal of coordination chemistry, 2013
New hexadentate nickel(II) complex Mg[Ni(1,3-pd3ap)]·10H2O containing unsymmetrical edta-type lig... more New hexadentate nickel(II) complex Mg[Ni(1,3-pd3ap)]·10H2O containing unsymmetrical edta-type ligand, 1,3-propanediamine-N,N,N′-triacetate-N′-3-propionate (1,3-pd3ap), has been prepared, chromatographically separated, and characterized. Only one [trans(O5)] of the two possible geometrical isomers was isolated. In this isomer, the two five-membered glycinate rings (R rings) occupy
trans-axial sites while the one glycinate ring and one β-alaninate ring lie in the equatorial plane
with the two diamine nitrogens (G rings). This result confirms the assignment made on the basis of
the density functional theory (DFT), IR, and UV–Vis spectral data analysis. In order to see cation
influence on the structural and electronic behavior, [Ni(H2O)6][Ni(1,3-pdta)]·2H2O complex has also been prepared and its structure verified by an X-ray analysis. Spectral data and electronic
transition assignment, DFT–natural bonding orbital, and an extensive strain analysis are discussed in comparison with those of other [Ni(edta-type)]2 complexes of known configuration.
Polyhedron, 2013
A new hexadentate chromium(III) complex, Na[Cr(l,3-pd3ap)]Á3H 2 O, containing an unsymmetrical ed... more A new hexadentate chromium(III) complex, Na[Cr(l,3-pd3ap)]Á3H 2 O, containing an unsymmetrical edta-type ligand, the 1,3-propanediam ine-N,N,N 0-triacetate-N 0-3-propionate ion (1,3-pd3ap), has been prepared, chromatographically separated and characterized. Only one [trans(O 5)] of the two possible geometrical isomers was isolated. In this isomer the two five-membered glycinate rings (R rings) occupy trans-axial sites, while the one glycinate ring and one b-alaninate ring lie in the equatorial plane wit h the two diamine nitrogens (G rings). This result confirms the assignment made on the basis of Density Functional Theory (DFT), IR and UV-Vis spectral data analyses. The spectral data and electron ic transition assignment, DFT-NBO, Ligand Field DFT and extensive strain analysis are discussed by a comparison with those of other [Cr(edta-type)] À complexes of known configurations. The stoichiometry and stability of the complexes formed between the chromiu m(III) ion and 1,3-propanediamine-N,N,N 0-triacetic-N 0-propionic acid (H 4 1,3-pd3ap) were determine d in aqueous solution by potentiometry at 25 °C and 0.1 M NaCl ionic strength. The existence of Cr(H n L), n = 0, 1, 2 and 3 type complexes were verified. The formation of the Cr(OH)L comp lex was observed at higher pH values. The concentration distribution diagra ms of the complexes were evaluated.
Chemistry select, 2020
Two new neutral ruthenium(II) complexes [Ru(η6-p-cymene) Cl2(1)] (3) and [Ru(η6-p-cymene)Cl2(2)]... more Two new neutral ruthenium(II) complexes [Ru(η6-p-cymene)
Cl2(1)] (3) and [Ru(η6-p-cymene)Cl2(2)] (4) (1=5-(phenylamino)-
3-pyrrolidin-1-ylisothiazole-4-carbonitrile; 2=3-morpholin-4-yl-
5-(phenylamino)isothiazole-4-carbonitrile) have been synthesized
and characterized using elemental analysis, IR, UV-Vis and
NMR spectroscopy. The crystal structure was confirmed for
complex 3 and both ligands. Examination of the interactions of
ligands and complexes with CT-DNA (Calf Thymus DNA), as
well as with HSA (Human Serum Albumin) revealed that ligands
and complexes could interact with CT-DNA through intercalation
and could bind strongly with HSA. Docking experiments
toward DNA dodecamer indicate excellent accordance with
experimental ΔG values. The cytotoxic activity of ligands and
complexes was evaluated by MTT assay against HCT116 and
HeLa tumoral cells. The complexes 3 and 4 showed good
activity and selectivity on HCT116 cells. Neither of the tested
compounds shows cytotoxic activity against a healthy MRC-
5 cell line. Flow cytometry analysis showed the apoptotic death
of the HCT116 cells with a cell cycle arrest in the S-phase.
Acta Horticulturae et Regiotecturae, May 23, 2023
Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family.... more Citrus aurantium amara (sour orange) belongs to one of the largest genera of the Rutaceae family. The species of this genus are
consumed worldwide as fresh or in form of beverages. They include well-known crops lemons, oranges, mandarins, grapefruits,
and limes. The industrial processing of these fruits produces high amounts of waste (around 50%) which is a valuable source
of essential oils. Since they are produced mainly from peel, considered waste, these essential oils have great economic value.
In that regard, the aim of this study was to evaluate the chemical composition of the essential oil obtained from the peel of
Citrus aurantium amara, as well as to assess the biological eff ects by the means of antioxidant and antibacterial activity. Results
of GC and GC/MS analysis characterized this EO as a valuable source of limonene found in the amount of 90.4% of the total.
Results of antioxidant activity indicate better inhibition of ABTS•+ (44.93 ±1.45%) compared to the DPPH• (11.03 ±1.08%). Moreover,
the results of the antimicrobial assessment using the disc diff usion method displayed low inhibition potency of this essential oil
towards G+ and G- bacteria and yeast strains.
Journal of the Serbian Chemical Society, 2022
Only one (trans(O5)-Na[Rh(ED3AP)]?3H2O) of possible two isomers was synthesized and characterized... more Only one (trans(O5)-Na[Rh(ED3AP)]?3H2O) of possible two isomers was synthesized and characterized by single crystal X-ray analysis, IR and UV?Vis spectroscopy. Computational analysis of both isomers was performed with three levels of theory (B3LYP/TZV, BP86/TZV, OPBE/TZV), which gave consistent results. The more stable isomer by total energy and ligand field stabilization energy (LFSE) was trans(O5) which appeared in synthesis. The calculation of excited state energies complied with UV?Vis spectra, especially with OPBE functional. The results of excited state energy pointed out the differences among isomers in means of a splitting pattern of 1T2g excited state term. Both isomers have a strongly delocalized structure, according to the natural bonding orbital (NBO) analysis. NBO analysis shows that the trans(O5) isomer is more stable than trans(O5O6) for approx. 87 kJ/mol. Therefore, only the trans(O5) isomer is present in the reaction mixture.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
University of Kragujevac, 2019
Within this PhD dissertation, the complexes of rhodium(III) with chelate polyaminopolycarboxylate... more Within this PhD dissertation, the complexes of rhodium(III) with chelate polyaminopolycarboxylate edta-type of ligands have been synthesized and characterized, among which are two neutral cis-equatorial-[Rh(ed3a)(H2O)] and cis-polar-[Rh(1,3-pd3a)(H2O)], as well as three anionic cis-equatorial-[Rh(ed3a)Cl]-, cis-polar-[Rh(1,3-pd3a)Cl]- and trans(O5O6)- [Rh(еddadp)]-. The synthesized rhodium(III) complexes were characterized by the use of standard methods (elemental microanalysis, melting point), as well as by modern spectroscopic analysis techniques (1H and 13C NMR, IR and UV-Vis). Structures of the synthesized complexes were determined by X-ray structural analysis, except in the case of cis-polar-[Rh(1,3-pd3a)(H2O)]∙2H2O complex. Its geometry is assumed based on spectral analysis, DFT calculations, as well as by comparison with similar complexes that are structurally characterized. The protonation constants of H3ed3a и H31,3-pd3a ligands, the stability constants of the complexes and the stoichiometry of the complexes with these ligands were studied in aqueous solution, whereby only mononuclear complexes have been confirmed: [MHL] ([Rh(Hed3a)]+, [Rh(H1,3-pd3a)]+), [ML] ([Rh(ed3a)], [Rh(1,3-pd3a)]) и [MLH-1] ([RhOH(ed3a)]-, [RhOH(1,3- pd3a)]-). The biological activity of these compounds in vitro was investigated using the MTT cytotoxicity test, as well as methods for the detection of apoptosis. The greatest cytotoxicity was demonstrated by the complex [Rh(ed3a)(H2O)]·H2O, while the most inactive was [Rh(1,3- pd3a)(H2O)]·2H2O, and the HeLa cell line is the most sensitive. The results of flow cytometry and Western blot analysis suggest apoptosis as the primary mode of cell death, in a caspase-dependent manner. Finally, computer methods were used to interpret the structural parameters of the experimentally obtained Rh(III) complexes, as well as their possible isomers. It was found that the B3LYP method is both numerically and visually most similar to experimental results obtained from X-ray structures. A detailed analysis of the energy dependence of geometric isomers on the usual deformation parameters ((Oh), (M-O-C), (N)) indicates the inability of the formation of trans(O6) isomer in the case of [M(eddadp)]- system. In the case of [М(1,3- pddadp)]- system low energy profile allows the formation of trans(O6) isomer for rhodium(III) complexes, while high energy of trans(O5)-[Co(1,3-pddadp)]- exclude the possibility for these complex to be formed. The boundary energy, beyond which it is impossible to expect the formation of geometric isomers, could have a value of about 6 kcal mol-1 for [Rh(eddadp)]- and [Rh (1,3-pddadp)]- systems. NBO and NRT analyzes of the [М(eddadp)]- and [М(1,3- pddadp)]- (M = Rh(III), Co(III)) systems show that all isomers are strongly delocalized structures, and all resulting resonant structures show that the metal ions are tri-coordinated through N2O or NO2 chromophores, except Co(III) in trans(O6)-[Co(eddadp)]- complex ion which adopts di-coordination in an octahedral surrounding. Also, covalency is more pronounced in the complexes of rhodium(III) than in the case of cobalt(III) complexes. The results of a computer simulated docking between the HSA and cis-equatorial- [Rh(ed3a)(H2O)] and cis-polar-[Rh(1,3-pd3a)(H2O)] complexes indicate that four hydrogen bonds make rhodium complex tightly bounded to HSA and quite safe for his transport to the target cells.