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Publikation

Pantelić, N. ?.; Božić, B.; Zmejkovski, B. B.; Banjac, N. R.; Dojčinović, B.; Wessjohann, L. A.; Kaluđerović, G. N.; In Vitro Evaluation of Antiproliferative Properties of Novel Organotin(IV) Carboxylate Compounds with Propanoic Acid Derivatives on a Panel of Human Cancer Cell Lines Molecules 26, 3199, (2021) DOI: 10.3390/molecules26113199

The synthesis of novel triphenyltin(IV) compounds, Ph3SnLn (n = 1–3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), HL1, and the new propanoic acid derivatives 3-(4,5-bis(4-methoxylphenyl)oxazol-2-yl)propanoic acid, HL2, and 3-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)propanoic acid, HL3, has been performed. The ligands represent commercial drugs or their derivatives and the tin complexes have been characterized by standard analytical methods. The in vitro antiproliferative activity of both ligands and organotin(IV) compounds has been evaluated on the following tumour cell lines: human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29), breast cancer (MCF-7), and hepatocellular cancer (HepG2), as well as on normal mouse embryonic fibroblast cells (NIH3T3) with the aid of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. Contrary to the inactive ligand precursors, all organotin(IV) carboxylates showed very good activity with IC50 values ranging from 0.100 to 0.758 µM. According to the CV assay (IC50 = 0.218 ± 0.025 µM), complex Ph3SnL1 demonstrated the highest cytotoxicity against the caspase 3 deficient MCF-7 cell line. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated a two-fold lower concentration of tin in MCF-7 cells in comparison to platinum. To investigate the mechanism of action of the compound Ph3SnL1 on MCF-7 cells, morphological, autophagy and cell cycle analysis, as well as the activation of caspase and ROS/RNS and NO production, has been performed. Results suggest that Ph3SnL1 induces caspase-independent apoptosis in MCF-7 cells.
Publikation

Pantelić, N. ?.; Zmejkovski, B. B.; Božić, B.; Dojčinović, B.; Banjac, N. R.; Wessjohann, L. A.; Kaluđerović, G. N.; Synthesis, characterization and in vitro biological evaluation of novel organotin(IV) compounds with derivatives of 2-(5-arylidene-2,4-dioxothiazolidin-3-yl)propanoic acid J. Inorg. Biochem. 211, 111207, (2020) DOI: 10.1016/j.jinorgbio.2020.111207

Two novel triphenyltin(IV) compounds, [Ph3SnL1] (L1 = 2-(5-(4-fluorobenzylidene)-2,4-dioxotetrahydrothiazole-3-yl)propanoate (1)) and [Ph3SnL2] (L2 = 2-(5-(5-methyl-2-furfurylidene)-2,4-dioxotetrahydrothiazole-3-yl)propanoate (2)) were synthesized and characterized by FT-IR, (1H and 13C) NMR spectroscopy, mass spectrometry, and elemental microanalysis. The in vitro anticancer activity of the synthesized organotin(IV) compounds was determined against four tumor cell lines: PC-3 (prostate), HT-29 (colon), MCF-7 (breast), and HepG2 (hepatic) using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. The IC50 values are found to be in the range from 0.11 to 0.50 μM. Compound 1 exhibits the highest activity toward PC-3 cells (IC50 = 0.115 ± 0.009 μM; CV assay). The tin and platinum uptake in PC-3 cells showed a threefold lower uptake of tin in comparison to platinum (as cisplatin). Together with its higher activity this indicates a much higher cell inhibition potential of the tin compounds (calculated to ca. 50 to 100 times). Morphological analysis suggested that the compounds induce apoptosis in PC-3 cells, and flow cytometry analysis revealed that 1 and 2 induce autophagy as well as NO (nitric oxide) production.
Publikation

Zmejkovski, B. B.; Pantelić, N.; Filipović, L.; Aranđelović, S.; Radulović, S.; Sabo, T. J.; Kaluđerović, G. N.; In Vitro Anticancer Evaluation of Platinum(II/IV) Complexes with Diisoamyl Ester of (S,S)-ethylenediamine-N,N’-di-2-propanoic Acid Anti-Cancer Agents Med. Chem. 17, 1136-1143, (2017) DOI: 10.2174/1871520616666161207155634

Aims: Platinum(II) and platinum(IV) complexes [PtCln{(S,S)-(i-Am)2eddip}] (n = 2, 4: 1, 2, respectively; (S,S)-(i-Am)2eddip = O,O’-diisoamyl-(S,S)-ethylenediamine-N,N’-di-2-propanoate) were synthesized and characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and mass spectrometry.Method: Quantum chemical calculations were used to predict formed isomers of 1 and 2. Furthermore, reduction of 2 with ascorbic acid was followed by time-dependant 13C NMR spectroscopy in order to enable assignation of the formed isomers for complex 1. In vitro cytotoxic activity was determined for 1 and 2 on a panel of five human tumor cell lines derived from cervix adenocarcinoma (HeLa), alveolar basal adenocarcinoma (A549), breast adenocarcinoma (MDA-453), colorectal cancer (LS 174), erythromyeloblastoid leukemia (K562), as well as one non-malignant human lung fibroblast cell line (MRC-5), using MTT assay. Result: Both complexes exhibited high (2 against K562: IC50 = 5.4 μM), more active than cisplatin, to moderate activity (1). Both complexes caused considerable decrease of cell number in K562 cells in G1, S and G2 phases, concordantly increasing subpopulation in sub-G1 fraction. Morphological analysis of K562 cell death induced by platinum(II/IV) complexes indicate apoptosis.
Publikation

Kaluđerović, G. N.; Bulatović, M.; Krajnović, T.; Paschke, R.; Zmejkovski, B. B.; Maksimović-Ivanić, D.; Mijatović, S.; (18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): Synthesis and In Vitro Antitumor Activity Inorganics 5, 56, (2017) DOI: 10.3390/inorganics5030056

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl)aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone.
Publikation

Pantelić, N.; Stanojković, T. P.; Zmejkovski, B. B.; Kaluđerović, G. N.; Sabo, T. J.; Antiproliferative Activity of Gold(III) Complexes with Esters of Cyclohexyl-Functionalized Ethylenediamine-N,N’-Diacetate Serb. J. Exp. Clin. Res. 18, 289-294, (2017) DOI: 10.1515/sjecr-2017-0067

Six gold(III) complexes with esters of cyclohexyl-functionalized ethylenediamine-N,N’-diacetate, general formula [AuCl2{(S,S)-R2eddch}]PF6, [(S,S)-eddch = (S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate, R = Me, Et, n-Pr, n-Bu, i-Bu, i-Am, 1–6, respectively], were tested against cancer cell lines such as human melanoma Fem-x, human colon carcinoma LS174T and non-small cell lung carcinoma A549 as well as a non-cancerous human embryonic lung fibroblasts MRC-5 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with the aim of assessing in vitro antitumoral activity and selectivity. All investigated complexes showed lower cytotoxicity and better or similar selectivity in comparison to cisplatin, used as reference compound. Complex [AuCl2{(S,S)-(i-Am)2eddch}]PF6 (6) demonstrated the highest activity against Fem-x (IC50 = 14.98 ± 0.34 μM). Additionally, the same complex expressed 4.5 times higher selectivity than cisplatin.
Publikation

Pantelić, N.; Zmejkovski, B. B.; Kolundžija, B.; Crnogorac, M. ?.; Vujić, J. M.; Dojčinović, B.; Trifunović, S. R.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N.; In vitro antitumor activity, metal uptake and reactivity with ascorbic acid and BSA of some gold(III) complexes with N,N′-ethylenediamine bidentate ester ligands J. Inorg. Biochem. 172, 55-66, (2017) DOI: 10.1016/j.jinorgbio.2017.04.001

Four novel gold(III) complexes of general formulae [AuCl2{(S,S)-R2eddl}]PF6 (R2eddl = O,O′-dialkyl-(S,S)-ethylenediamine-N,N′-di-2-(4-methyl)pentanoate, R = n-Pr, n-Bu, n-Pe, i-Bu; 1–4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N′-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24 h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC50: 5.04–6.51 μM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner.
Publikation

Pantelić, N.; Stanković, D. M.; Zmejkovski, B. B.; Kaluđerović, G. N.; Sabo, T. J.; Electrochemical properties of some gold(III) complexes with (S,S)-R2edda-type ligands Int. J. Electrochem. Sci. 11, 1162-1171, (2016)

Oxidation-reduction properties of eleven gold(III) complexes with (S,S)-R2edda-type ligands was studied by cyclic and differential pulse voltammetry in DMSO. Series I: [AuCl2{(S,S)-R2eddip}]PF6, (S,S)-eddip = (S,S)-ethylenediamine-N,N’-di-2-propanoate, R = n-butyl, n-pentyl, isobutyl, isoamyl, cyclopentyl, 1–5; II: [AuCl2{(S,S)-R2eddch}]PF6, (S,S)-eddch = (S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate, R = methyl, ethyl, n-propyl, n-butyl, isobutyl, isoamyl, 6–11. Voltammograms in DMSO showed two successive irreversible reduction steps, where AuI species were the final reduction product. Reduction potential values are in range from 116 to 156 mV (Ep1) and –520 to –572 mV (Ep2) for Series I and from 148 to 228 mV (Ep1) and –569 to –638 mV (Ep2) for Series II. In general, slightly easier reduction of complexes belonging to Series I (higher cytotoxicity) could be due to less steric hindrance around the gold center. Reduction potentials and anticancer activity are not in correlation.
Publikation

Pantelić, N.; Zmejkovski, B. B.; Marković, D. D.; Vujić, J. M.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N.; Synthesis, Characterization, and Cytotoxicity of a Novel Gold(III) Complex with O,O′-Diethyl Ester of Ethylenediamine-N,N′-Di-2-(4-Methyl)Pentanoic Acid Metals 6, 226, (2016) DOI: 10.3390/met6090226

A novel gold(III) complex, [AuCl2{(S,S)-Et2eddl}]PF6, ((S,S)-Et2eddl = O,O′-diethyl ester of ethylenediamine-N,N′-di-2-(4-methyl)pentanoic acid) was synthesized and characterized by IR, 1D (1H and 13C), and 2D (H,H-COSY and H,H-NOESY) NMR spectroscopy, mass spectrometry, and elemental analysis. Density functional theory calculations confirmed that (R,R)-N,N′ diastereoisomer was energetically the most stable isomer. In vitro antitumor action of ligand precursor [(S,S)-H2Et2eddl]Cl2 and corresponding gold(III) complex was determined against tumor cell lines: human adenocarcinoma (HeLa), human colon carcinoma (LS174), human breast cancer (MCF7), non-small cell lung carcinoma cell line (A549), and non-cancerous cell line human embryonic lung fibroblast (MRC-5) using microculture tetrazolium test (MTT) assay. The results indicate that both ligand precursor and gold(III) complex have showed very good to moderate cytotoxic activity against all tested malignant cell lines. The highest activity was expressed by [AuCl2{(S,S)-Et2eddl}]PF6 against the LS174 cells, with IC50 value of 7.4 ± 1.2 µM.
Publikation

Pantelić, N.; Stanojković, T. P.; Zmejkovski, B. B.; Sabo, T. J.; Kaluđerović, G. N.; In vitro anticancer activity of gold(III) complexes with some esters of (S,S)-ethylenediamine-N,N′-di-2-propanoic acid Eur. J. Med. Chem. 90, 766-774, (2015) DOI: 10.1016/j.ejmech.2014.12.019

Five novel gold(III) complexes of general formulas [AuCl2{(S,S)-R2eddip}]PF6, ((S,S)-eddip = (S,S)-ethylenediamine-N,N′-di-2-propanoate, R = n-Bu, n-Pe, i-Bu, i-Am, cPe; 1–5, respectively) were synthesized and characterized by UV/Vis, IR and NMR spectroscopy and mass spectrometry. DFT calculations indicated that (R,R)-N,N′-configuration diastereoisomers were the most stable for 1–5. 3 is stable in DMSO for at least 24 h, but immediate hydrolysis in PBS occurs. 3 is readily reduced with ascorbic acid and forms adducts with bovine serum albumin (BSA). In vitro anticancer activity of the gold(III) complexes against human cervix adenocarcinoma HeLa, human myelogenous leukemia K562, human melanoma Fem-x tumor cell lines, as well as against non-cancerous human embryonic lung fibroblast cell line MRC-5 was determined using MTT assay. Complex 4 showed highest activity and selectivity (IC50(Fem-x) = 1.3 ± 0.2; IC50(MRC-5)/IC50(Fem-x) = 72.5 ± 12.4), 4 times more active and 28 times more selective than cisplatin. Complexes induced apoptotic mode of death in a time-dependent manner in HeLa cells.
Publikation

Bulatović, M.; Kaluđerović, M. R.; Mojić, M.; Zmejkovski, B. B.; Hey-Hawkins, E.; Vidaković, M.; Grdović, N.; Kaluđerović, G. N.; Mijatović, S.; Maksimović-Ivanić, D.; Improved in vitro antitumor potential of (O,O′-Diisobutyl-ethylenediamine-N,N′-di-3-propionate)tetrachloridoplatinum(IV) complex under normoxic and hypoxic conditions Eur. J. Pharmacol. 760, 136-144, (2015) DOI: 10.1016/j.ejphar.2015.04.012

(O,O′-Diisobutyl-ethylenediamine-N,N′-di-3-propionate)tetrachloridoplatinum(IV), [PtCl4(iBu2eddp)], shows an improved pharmacological profile in comparison to cisplatin. This is manifested through accelerated dying process led by necrotic cell death, reflected through mitochondrial collapse, strong ATP depletion and reactive oxygen species production. Loss of mitochondrial potential was further followed with intensive apoptosis that finalized with DNA fragmentation.Different dynamic of tumoricidal action could be partly ascribed to less affected repair mechanisms in comparison to cisplatin. Importantly, [PtCl4(iBu2eddp)] did not induce necrosis in primary fibroblasts suggesting different intracellular response of normal vs. tumor cells. This selectivity toward malignant phenotype is further confirmed by retained tumoricidal potential in hypoxic conditions, while cisplatin became completely inefficient.

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