Publications by authors named "Justyn Ochocki"

35 Publications

Synthesis, Spectroscopy, Single-Crystal Structure Analysis and Antibacterial Activity of Two Novel Complexes of Silver(I) with Miconazole Drug.

Int J Mol Sci 2021 Feb 3;22(4). Epub 2021 Feb 3.

Department of Bioinorganic Chemistry, Chair of Medicinal Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

In a previous article, we reported on the higher toxicity of silver(I) complexes of miconazole [Ag(MCZ)NO ()] and [Ag(MCZ)ClO ()] in HepG2 tumor cells compared to the corresponding salts of silver, miconazole and cisplatin. Here, we present the synthesis of two silver(I) complexes of miconazole containing two new counter ions in the form of Ag(MCZ)X (MCZ = 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole]; X = BF (), SbF ()). The novel silver(I) complexes were characterized by elemental analysis, H NMR, C NMR and infrared (IR) spectroscopy, electrospray ionization (ESI)-MS spectrometry and X-ray-crystallography. In the present study, the antimicrobial activity of all obtained silver(I) complexes of miconazole against six strains of Gram-positive bacteria, five strains of Gram-negative bacteria and yeasts was evaluated. The results were compared with those of a silver sulfadiazine drug, the corresponding silver salts and the free ligand. Silver(I) complexes exhibited significant activity against Gram-positive bacteria, which was much better than that of silver sulfadiazine and silver salts. The highest antimicrobial activity was observed for the complex containing the nitrate counter ion. All Ag(I) complexes of miconazole resulted in much better inhibition of yeast growth than silver sulfadiazine, silver salts and miconazole. Moreover, the synthesized silver(I) complexes showed good or moderate activity against Gram-negative bacteria compared to the free ligand.
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http://dx.doi.org/10.3390/ijms22041510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919260PMC
February 2021

Light Stability, Pro-Apoptotic and Genotoxic Properties of Silver (I) Complexes of Metronidazole and 4-Hydroxymethylpyridine against Pancreatic Cancer Cells In Vitro.

Cancers (Basel) 2020 Dec 20;12(12). Epub 2020 Dec 20.

Departament of Bioinorganic Chemistry, Chair of Medicinal Chemistry, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland.

Antimicrobial properties of silver (I) ion and its complexes are well recognized. However, recent studies suggest that both silver (I) ion and its complexes possess anticancer activity associated with oxidative stress-induced apoptosis of various cancer cells. In this study, we aimed to investigate whether silver nitrate and its complexes with metronidazole and 4-hydroxymethylpyridine exert anticancer action against human pancreatic cancer cell lines (PANC-1 and 1.2B4). In the study, we compared decomposition speed for silver complexes under the influence of daylight and UV-A (ultraviolet-A) rays. We employed the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide) assay to evaluate the cytotoxicity and the alkaline comet assay to determine genotoxicity of silver nitrate and its complexes. Flow cytometry and the Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of human pancreatic cancer cells. We found a dose dependent decrease of both pancreatic cancer cell line viability after exposure to silver nitrate and its complexes. The flow cytometry analysis confirmed that cell death occurred mainly via apoptosis. We also documented that the studied compounds induced DNA damage. Metronidazole and 4-hydroxymethylpyridine alone did not significantly affect viability and level of DNA damage of pancreatic cancer cell lines. Complex compounds showed better stability than AgNO, which decomposed slower than when exposed to light. UV-A significantly influences the speed of silver salt decomposition reaction. To conclude, obtained data demonstrated that silver nitrate and its complexes exerted anticancer action against human pancreatic cancer cells.
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http://dx.doi.org/10.3390/cancers12123848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767315PMC
December 2020

Synthesis, Spectroscopy, Light Stability, Single-Crystal Analysis, and In Vitro Cytotoxic Activity on HepG2 Liver Cancer of Two Novel Silver(I) Complexes of Miconazole.

Int J Mol Sci 2020 May 21;21(10). Epub 2020 May 21.

Department of Bioinorganic Chemistry, Chair of Medicinal Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

Two novel silver(I) complexes of the biologically active ligand miconazole in the form of Ag(MCZ)X (MCZ = 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1-imidazole]; X = NO (), ClO ()) were synthesized and fully characterized. The complexes were obtained by reactions of Ag(I) salts with miconazole (MCZ). Silver(I) complexes were characterized by elemental analysis, H-NMR and infrared (IR) spectroscopy, electrospray ionization (ESI)-MS spectrometry, and X-ray-crystallography. This work also presents a cytotoxicity study of the silver(I) complexes of miconazole and appropriate silver(I) salts using Balb/c 3T3 and HepG2 cell lines. The cytotoxicity of the compounds was assessed based on four biochemical endpoints: lysosomal activity (neutral red uptake (NRU) assay), mitochondrial activity (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay), total protein content (TPC assay), and cellular membrane integrity (lactate dehydrogenase (LDH) assay). The cancer HepG2 cells were more sensitive to the complexes tested, and the most affected endpoint was cellular membrane damage compared to Balb/c 3T3 fibroblasts. Moreover, study complexes inhibited the growth of cancer cells at submicromolecular concentrations (0.26-0.47 μM) lower than that required for the anticancer agent, cisplatin, in MTT, NRU, and TPC assays. Both complexes were characterized by higher toxicity to human cancer cells (HepG2) than silver(I) salts and the free ligand. Combination of Ag(I) salts with miconazole is associated with the marked improvement of cytotoxic activities that can be considered as the significant point in the construction of a new generation of antineoplastic agents.
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http://dx.doi.org/10.3390/ijms21103629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279231PMC
May 2020

Effect of treatment with silver(I) complex of metronidazole on ocular rosacea: Design and formulation of new silver drug with potent antimicrobial activity.

J Trace Elem Med Biol 2020 Apr 17;61:126531. Epub 2020 Apr 17.

Department of Bioinorganic Chemistry, Chair of Medicinal Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland. Electronic address:

Background: Metronidazole with well-soluble silver nitrate forms a complex with potent activity (synergism) against bacterial strains and fungi with simultaneous lower side effect than in the case of the two agents administered separately. This study aimed to establish effectiveness in the treatment of ocular rosacea with new formulation of drops and ointment with silver(I) complex of metronidazole.

Methods: Three patients suffering from serious ophthalmic complications of acne rosacea were treated with drops and ointments applied 3 times a day for 3 months. The uncorrected visual acuity testing (UCVA), pachymetry as well as subjective and objective tear film assessment were evaluated.

Results: In all patients, we have improved UCVA as well as objective and subjective evaluation of the tear film parameters. No significant differences in corneal thickness were observed.

Conclusion: Well soluble silver(I) complex of metronidazole might be an alternative method in ophthalmic complications of acne rosacea treatment.
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http://dx.doi.org/10.1016/j.jtemb.2020.126531DOI Listing
April 2020

Simple -Platinum Complex Bearing 3-Aminoflavone Ligand Could Be a Useful Drug: Structure-Activity Relationship of Platinum Complex in Comparison with Cisplatin.

Int J Mol Sci 2020 Mar 19;21(6). Epub 2020 Mar 19.

Department of Bioinorganic Chemistry, Medical University of Lodz, 1 Muszynskiego St., 90-151 Łódź, Poland.

Following previous studies devoted to -Pt(3-af)Cl, in this paper, the molecular structure and intermolecular interactions of the title complex are compared with other cisplatin analogues of which the crystal structures are presented in the Cambridge Structural Database (CSD). Molecular Hirshfeld surface analysis and computational methods were used to examine a possible relationship between the structure and anticancer activity of -Pt(3-af)Cl. The purpose of the article was also to investigate the effect of hyperthermia on the anticancer activity of cisplatin, cytostatics used in the treatment of patients with ovarian cancer and a new analogue of cisplatin--Pt(3-af)Cl. The study was conducted on two cell lines of ovarian cancer sensitive to Caov-3 cytostatics and the OVCAR-3 resistant cisplatin line. The study used the MTT (3-(4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide) cell viability assay, LDH (lactate dehydrogenase), and the quantitative evaluation method for measuring gene expression, i.e., qPCR with TagMan probes. Reduced survivability of OVCAR-3 and Caov-3 cells exposed to cytostatics at elevated temperatures (37 °C, 40 °C, 43 °C) was observed. Hyperthermia may increase the sensitivity of cells to platinum-based antineoplastic drugs and paclitaxel, which may be associated with the reduction of gene expression related to apoptotic processes.
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http://dx.doi.org/10.3390/ijms21062116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139614PMC
March 2020

Increased Temperature Facilitates Adeno-Associated Virus Vector Transduction of Colorectal Cancer Cell Lines in a Manner Dependent on Heat Shock Protein Signature.

Biomed Res Int 2020 8;2020:9107140. Epub 2020 Feb 8.

Department of Applied Pharmacy, Faculty of Pharmacy with Laboratory Medicine, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.

Colorectal cancer (CRC) is one of the most common cancers in human population. A great achievement in the treatment of CRC was the introduction of targeted biological drugs and solutions of chemotherapy, combined with hyperthermia. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) extends the patients' survival with CRC. Recently, gene therapy approaches are also postulated. The studies indicate the possibility of enhancing the gene transfer to cells by recombinant adeno-associated vectors (rAAV) at hyperthermia. The rAAV vectors arouse a lot of attention in the field of cancer treatment due to many advantages. In this study, the effect of elevated temperature on the transduction efficiency of rAAV vectors on CRC cells with different origin and gene profile was examined. The effect of heat shock on the penetration of rAAV vectors into CRC cells in relation with the expression of HSP and AAV receptor genes was tested. It was found that the examined cells under hyperthermia (43°C, 1 h) are transduced at a higher level than in normal conditions (37°C). The results also indicate that studied RKO, HT-29, and LS411N cell lines express HSP genes at different levels under both 37°C and 43°C. Moreover, the results showed that the expression of AAV receptors increases in response to elevated temperature. The study suggests that increased rAAV transfer to CRC can be achieved under elevated temperature conditions. The obtained results provide information relevant to the design of new solutions in CRC therapy based on the combination of hyperthermia, chemotherapy, and gene therapy.
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http://dx.doi.org/10.1155/2020/9107140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031720PMC
November 2020

Fluorimetric Properties of 3-Aminoflavone Biomolecule (3-AF). X-ray Crystal Structure of New Polymorph of 3-AF.

Molecules 2019 Aug 13;24(16). Epub 2019 Aug 13.

Department of Bioinorganic Chemistry, 1 Muszyńskiego Str., Medical University of Lodz, 90-151 Lodz, Poland.

The crystal structure of the new polymorphic form of 3-aminoflavone (3-AF) has been determined by single crystal X-ray diffraction. This report presents results of fluorimetric studies on 3-AF in methanol and aquatic solvents. Based on 3D fluorescence emission spectra, optimal values for excitation (λ) and emission/analytical (λ) wavelength, the analytical concentration range as well as the range of concentration quenching for the studied compound were established. Moreover, the limit of detection (LOD) and the limit of quantification (LOQ) were determined. The results were compared with those obtained using the standard UV-Vis absorption spectrophotometric method. The effect of acidity (pH) and the concentration of halide anions (chlorides, bromides, iodides and fluorides) on fluorescence quenching were analysed.
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http://dx.doi.org/10.3390/molecules24162927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719987PMC
August 2019

Silver(I) Complexes of the Pharmaceutical Agents Metronidazole and 4-Hydroxymethylpyridine: Comparison of Cytotoxic Profile for Potential Clinical Application.

Molecules 2019 May 21;24(10). Epub 2019 May 21.

Department of Bioinorganic Chemistry, Chair of Medicinal Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

In previous papers, we have reported on the high antifungal and significant antibacterial activity against Gram-positive and Gram-negative bacteria of the water-soluble silver(I) complexes of metronidazole and derivatives of pyridine compared to silver nitrate. In the present study, the cytotoxic activity of the silver(I) complexes of metronidazole and 4-hydroxymethylpyridine was compared with that of silver nitrate. Metronidazole and 4-hydroxymethylpyridine were investigated using Balb/c 3T3 and HepG2 cell lines in order to evaluate the potential clinical application of silver(I) complexes. The cells were exposed for 72 h to compounds at eight concentrations. The cytotoxic concentrations (IC) of the study compounds were assessed within four biochemical endpoints: mitochondrial activity, lysosomal activity, cellular membrane integrity, and total protein content. The investigated silver(I) complexes displayed comparable cytotoxicity to that of silver nitrate used in clinics. Mean cytotoxic concentrations calculated for investigated silver(I) complexes from concentration-response curves ranged from 2.13 to 26.5 µM. HepG2 cells were less sensitive to the tested complexes compared to fibroblasts (Balb/c 3T3). However, the most affected endpoint for HepG2 cells was cellular membrane damage. The cytotoxicity of both silver complexes was comparable for Balb/c 3T3 cells. The cytotoxic potential of the new silver(I) compounds compared to that of silver nitrate used in medicine indicates that they are safe and could be used in clinical practice. The presented results are yet more stimulating to further studies that evaluate the therapeutic use of silver complexes.
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http://dx.doi.org/10.3390/molecules24101949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572996PMC
May 2019

Synthesis, Spectroscopic Analysis and Assessment of the Biological Activity of New Hydrazine and Hydrazide Derivatives of 3-Formylchromone.

Molecules 2018 Aug 17;23(8). Epub 2018 Aug 17.

Department of Bioinorganic Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

The hydrazine and hydrazide derivatives of benzo-γ-pyrones with fluorine substituents remain an unexplored group of chemical compounds. This preliminary study reports the synthesis, structural assessment, initial microbiological screening and biological testing of the synthesized compounds on cell lines using the XTT-assay. A series of 10 novel hydrazine and hydrazide derivatives of 3-formylchromone were synthesized and their structures determined. Structural assessment consisted of elemental analysis, IR, ¹H-NMR, C-NMR, MS and crystallographic studies. Antimicrobial activity was tested on standard strains representing different groups of microorganisms. The tested compounds were found to inhibit microbial growth. Concentrations of 0.01⁻1250 µmol/L were found to influence cell proliferation, demonstrating antiproliferative and stimulation of proliferation against two cell lines: the L929 cell line (mouse fibroblast cell line) and the EA.hy926 cell line (the human umbilical vein, somatic cell hybrid).
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http://dx.doi.org/10.3390/molecules23082067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222780PMC
August 2018

Anticancer activity of a trans-platinum(II) complex of 3-aminoflavone to ovarian cancer cells.

Ginekol Pol 2017 ;88(2):68-74

Department of Applied Pharmacy, Medical University of Warsaw, Poland.

Objectives: Cisplatin is a classical anticancer drug used in the treatment of ovarian cancer. Unfortunately, the treatment is associated with numerous adverse effects. Studies concerning new platinum derivatives with less organ toxicity are conducted. The aim of this study was to analyse the effect of a new trans-platinum(II) complex of 3-aminoflavone on the viability and mortality of the cells from OVCAR 3 and CAOV 3 ovarian cancer cell lines and on the expression of the selected genes involved in the process of apoptosis.

Material And Methods: The viability of ovarian cancer cells and the cytotoxicity of a trans-platinum(II) complex of 3-amino-flavone: [trans-Pt(3-af )₂Cl₂), trans-bis-(3-aminoflavone) dichloridoplatinum(II)] and cisplatin were analysed using a spectrophotometric method with the use of MTT assay and LDH assay. BAX, BCL2, BIRC5 gene expression analysis on mRNA level was conducted with the use of Real-Time PCR method.

Results: It was observed that parallel to an increase in the concentration of the new complex compound and cisplatin there is a decrease in viability and an increase in mortality of ovarian cancer cells. As a result of exposure to the studied compound and cisplatin, an increased BAX gene expression and decreased BCL2 and BIRC5 gene expression were observed in the studied ovarian cancer cell lines.

Conclusion: Trans-Pt(3-af )₂Cl₂ exhibits anticancer activity towards OVCAR 3 and CAOV 3 ovarian cancer cell lines. The studied complex compound can be considered as a potential anticancer drug.
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http://dx.doi.org/10.5603/GP.a2017.0014DOI Listing
July 2018

New Look on 3-Hydroxyiminoflavanone and Its Palladium(II) Complex: Crystallographic and Spectroscopic Studies, Theoretical Calculations and Cytotoxic Activity.

Molecules 2016 Apr 13;21(4):455. Epub 2016 Apr 13.

Department of Bioinorganic Chemistry, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, Poland.

This work presents the synthesis, spectroscopic properties and single-crystal X-ray examination of the structure of 3-hydroxyiminoflavanone and its palladium complex. It presents the results of NMR (Nuclear Magnetic Resonance) spectroscopy, electron-density studies based on X-ray wavefunction refinement and theoretical calculations combined with QTAIM (Quantum Theory of Atoms in Molecules) and ELI-D (Electron Localizability Indicator) analyses. These offer an interesting new insight into the structures and behavior of flavanone and its complex, in solid state and in solution. The study also examines the cytotoxicity of the ligand and its complex against three human ovarian and lung cancer cell lines.
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http://dx.doi.org/10.3390/molecules21040455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273555PMC
April 2016

Antibacterial Activity and Cytotoxicity of Silver(I) Complexes of Pyridine and (Benz)Imidazole Derivatives. X-ray Crystal Structure of [Ag(2,6-di(CH2OH)py)2]NO3.

Molecules 2016 Jan 28;21(2):87. Epub 2016 Jan 28.

Department of Bioinorganic Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

Selected aspects of the biological activity of a series of six nitrate silver(I) complexes with pyridine and (benz)imidazole derivatives were investigated. The present study evaluated the antibacterial activities of the complexes against three Gram-negative strains: Pseudomonas aeruginosa ATCC 15442, Escherichia coli ATCC 25922 and Proteus hauseri ATCC 13315. The results were compared with those of silver nitrate, a silver sulfadiazine drug and appropriate ligands. The most significant antibacterial properties were exerted by silver(I) complexes containing benzimidazole derivatives. The cytotoxic activity of the complexes was examined against B16 (murine melanoma) and 10T1/2 (murine fibroblasts) cells. All of the tested silver(I) compounds were not toxic to fibroblast cells in concentration inhibited cancer cell (B16) viability by 50%, which ranged between 2.44-28.65 µM. The molecular and crystal structure of silver(I) complex of 2,6-di(hydroxymethyl)pyridine was determined by single-crystal X-ray diffraction analysis. The most important features of the crystal packing and intermolecular non-covalent interactions in the Ag(I) complex were quantified via Hirshfeld surface analysis.
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http://dx.doi.org/10.3390/molecules21020087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274122PMC
January 2016

Synthesis, characterization and antimicrobial activity of water-soluble silver(i) complexes of metronidazole drug and selected counter-ions.

Dalton Trans 2015 May;44(17):8178-89

Department of Bioinorganic Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

A series of water-soluble silver(i) complexes of the type [Ag(MTZ)2X] [MTZ = 1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole (metronidazole drug); X = NO3(-), ClO4(-), CF3COO(-), BF4(-) and CH3SO3(-)] was synthesised by the reactions of various Ag(i) salts with metronidazole (MTZ). All the complexes were characterized by ESI-MS spectrometry, solution NMR ((1)H and (13)C) and IR spectroscopy, and elemental analysis. Further evidence for the formation and molecular structure of all the complexes was provided by X-ray single-crystal crystallography. The different counter ions affect the crystal packing of the complexes and thus have an impact on the final geometries. The antimicrobial activities of the complexes against two Gram-positive strains: Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, three Gram-negative strains: Pseudomonas aeruginosa ATCC 15442, Escherichia coli ATCC 25922, Proteus hauseri ATCC 13315 and yeast Candida albicans ATCC 10231 were evaluated and compared with antibacterial and antifungal properties of appropriate silver salts, metronidazole and silver sulfadiazine drugs. The newly synthesized compounds exhibited significant antibacterial activity against Gram-positive bacteria, better than the referenced silver sulfadiazine. The best active silver(i)-metronidazole complex contains a methanesulphonate counter-ion. Moreover, the complex inhibited the growth of yeast Candida albicans at a concentration 3-fold lower than that required for silver sulfadiazine. In addition, the complexes containing a tetrafluoroborate and a perchlorate as counter-ions were characterized as effective antibacterial agents against the tested Gram-negative bacteria.
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http://dx.doi.org/10.1039/c5dt00403aDOI Listing
May 2015

trans-Platinum(II) complex of 3-aminoflavone - synthesis, X-ray crystal structure and biological activities in vitro.

Dalton Trans 2015 Jan;44(3):938-47

Department of Bioinorganic Chemistry, 1 Muszyńskiego St., Medical University, 90-151 Łódź, Poland.

This paper describes the synthesis of trans-bis-(3-aminoflavone)dichloridoplatinum(ii) (trans-Pt(3-af)2Cl2; TCAP) for use as a potential anticancer compound, and the evaluation of its structure by elemental and spectral analyses, and X-ray crystallography. The complex demonstrated a significant cytotoxic effect against human and murine cancer cell lines, as well as weaker toxicity towards healthy cells (human peripheral blood lymphocytes) in comparison with cisplatin. Various biochemical and morphological methods confirm that the proapoptotic activity of trans-Pt(3-af)2Cl2 is markedly higher than the reference cisplatin. Our results suggest that trans-Pt(3-af)2Cl2 may have a different antitumour specificity from that of cisplatin.
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http://dx.doi.org/10.1039/c4dt01501kDOI Listing
January 2015

Synthesis, characterization, and antimicrobial activity of silver(I) and copper(II) complexes of phosphate derivatives of pyridine and benzimidazole.

ChemMedChem 2014 Jan 11;9(1):169-76. Epub 2013 Nov 11.

Department of Bioinorganic Chemistry, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź (Poland).

Two silver(I) complexes--[Ag(4-pmOpe)]NO₃}(n) and [Ag(2-bimOpe)₂]NO₃--and three copper(II) complexes--[Cu₄Cl₆O(2-bimOpe)₄], [CuCl₂(4-pmOpe)₂], and [CuCl₂(2-bis(pm)Ope]--were synthesized by reaction of silver(I) nitrate or copper(II) chloride with phosphate derivatives of pyridine and benzimidazole, namely diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe), 1H-benzimidazol-2-ylmethyl diethyl phosphate (2-bimOpe), and ethyl bis(pyridin-2-ylmethyl)phosphate (2-bis(pm)Ope). These compounds were characterized by ¹H, ¹³C, and ³¹P NMR as well as IR spectroscopy, elemental analysis, and ESIMS spectrometry. Additionally, molecular and crystal structures of {[Ag(4-pmOpe)]NO₃}n and [Cu₄Cl₆O(2-bimOpe)₄] were determined by single-crystal X-ray diffraction analysis. The antimicrobial profiles of synthesized complexes and free ligands against test organisms from the ATCC and clinical sources were determined. Silver(I) complexes showed good antimicrobial activities against Candida albicans strains (MIC values of ∼19 μM). [Ag(2-bimOpe)₂]NO₃ was particularly active against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus epidermidis, with MIC values of ∼5 and ∼10 μM, respectively. Neither copper(II) complexes nor the free ligands inhibited the growth of test organisms at concentrations below 500 μg mL⁻¹.
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http://dx.doi.org/10.1002/cmdc.201300333DOI Listing
January 2014

Evaluation of cytotoxicity of new trans-palladium(II) complex in human cells in vitro.

Acta Pol Pharm 2011 Jan-Feb;68(1):127-36

Laboratory of Cytogenetics, University of Lodz, 12/16 Banacha St., 90-237 Łódź, Poland.

Studies of cytotoxicity allow to elucidate the mechanisms by which chemical compounds influence cells and tissues. On the basis of the structural analogy between platinum(II) and palladium(II) complexes, a variety of studies on palladium(II) compounds as potential anticancer drugs have been carried out (1, 2). The cytotoxicity was evaluated by MTT assay. Abilities of trans-palladium(II) complex containing diethyl (pyridin-2-ylmethyl)phosphates as non-leaving ligands (trans-[PdCl2(2-pmOpe 2)]) to induce apoptosis and necrosis in normal lymphocytes, A549 cells and HT29 cell lines were performed by use of fluorochrome staining. The obtained results revealed, that the new trans-palladium(II) complex was more cytotoxic against A549 and HT29 tumor cells than on the normal lymphocytes in vitro. The novel complex induces apoptosis in all tested cells, but in lymphocytes to a lesser degree. The compound tested also induced significant amounts of necrotic cells, which exceeded the level of apoptotic cell fractions. The results demonstrate that the trans-Pd(II) complex showed substantial cytotoxic activity against A549 and HT29 tumor cells and indicate that the new trans-palladium(II) complex effectively inhibited cancer cells growth.
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May 2011

Proapoptotic activity in vitro of two novel ruthenium(II) complexes with flavanone-based ligands that overcome cisplatin resistance in human bladder carcinoma cells.

J Inorg Biochem 2011 Apr 30;105(4):518-24. Epub 2010 Dec 30.

Department of Bioinorganic Chemistry, Medical University, Muszynskiego 1, Lodz, Poland.

In this study we examined their proapoptotic activity of cis-dichloridobis(3-imino-2-methoxyflavanone)ruthenium(II)3H(2)O (1) and cis-dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(II)2H(2)O (2) towards human bladder carcinoma cell line EJ and its cisplatin resistant subline EJcisR. On the basis of the experiments we carried out, it may be concluded, that: CDDP (cis-diamminedichloridoplatinum) resistance of EJcisR cells is probably based on partial loss of apoptotic pathway activating caspase-8 and increased resistance to DNA strand breaks and/or alkali-labile sites. Increased glutathione levels, as well as activity of P-gp transporter seems to be not relevant in this case. The proapoptotic activity of the ruthenium compounds is higher than that of cisplatin. Higher proapoptotic activity of 1 and 2 when compared to CDDP may be due to the presence of large, lipophilic flavanone-based ligands that may facilitate their trans-membrane transport and their redox activity. 1 and 2 induce apoptosis apparently in more than one way. Although caspase-8 activation and DNA strand breaks and/or alkali-labile sites are caused by the compounds, their ability to cause the oxidative stress in the cells may also participate in apoptosis induction.
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http://dx.doi.org/10.1016/j.jinorgbio.2010.12.013DOI Listing
April 2011

Synthesis, single-crystal and solution structure analysis and in vitro cytotoxic activity of two novel complexes of ruthenium(II) with in situ formed flavanone-based ligands.

Dalton Trans 2010 Oct 7;39(40):9711-8. Epub 2010 Sep 7.

Department of Bioinorganic Chemistry, Medical University, Muszynskiego 1, 90-151, Łódź, Poland.

Synthesis, structure and properties of two new flavanone complexes of Ru(ii) are described. The new complexes form during the reaction of ruthenium(iii) chloride with 3-aminoflavone (3-af) dissolved in an aliphatic alcohol. The formed products depend on the alcohol used and were found to be: cis-dichloridobis(3-imino-2-methoxyflavanone)ruthenium(ii)·3H(2)O (1) from a methanolic solution and cis-dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(ii)·2H(2)O (2) from an ethanolic solution, in which the original ligand 3-af had been converted by dehydrogenative alcoholysis to an entirely new ligand. This paper presents the X-ray structure and detailed (1)H-NMR analysis of both new compounds, as well as the study of their antiproliferative activity. The coordination of Ru(ii) is octahedral with [RuCl(2)N(2)O(2)] chromophores, having trans chlorides and common Ru-L distances. Both 1 and 2 are highly cytotoxic towards the cisplatin resistant EJ and L1210 cell lines, and both complexes are as active as cisplatin in the sensitive cell lines. They display the ability to overcome cisplatin resistance in the drug resistant sub-lines EJcisR and L1210R. The present evidence suggests that the mechanism of biological activity may be different for these ruthenium compounds compared to cisplatin.
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http://dx.doi.org/10.1039/c0dt00535eDOI Listing
October 2010

Structure-activity relationship and apoptosis induction in A549 cells by the potential anticancer compound cis-bis(3-aminoflavone)dichloroplatinum(II).

Arzneimittelforschung 2010 ;60(3):149-56

Department of Cytogenetics and Plant Molecular Biology, University of Lodz, Lodz, Poland.

cis-DDP (cis-diamminedichloroplatinum(II), CAS 15663-27-1) is widely used in chemotherapy of many types of cancer. However, besides effectiveness, it gives many side effects which limit its clinical application. Therefore, nowadays studies are focused on searching for novel analogs of cis-DDP, at least equally effective in chemotherapy but less toxic. One of them might be cis-BAFDP (cis-bis(3-aminoflavone)dichloroplatinum(II)) with one of the hydrogen atoms of the amino group of cis-DDP replaced by a flavone ring. 3-Aminoflavone (AF) which posseses the desired NH2 group has been used as non-leaving ligand. The complex has been obtained in the reaction of AF and K2PtCl4. There are no data concerning evaluation of structural studies of cis-BAFDP, the beneficial anticancer properties of which were proved in vitro and in vivo. Therefore it was worthwhile to undertake a confirmation of the chemical structure of this compound by applying various spectroscopic techniques especially because of its potential pharmacological application. With this aim in mind this compound was characterized by: IR, 1H NMR, 195Pt NMR, UV absorption and fluorescence spectroscopy. Moreover, stronger apoptosis induction by cis-BAFDP than cis-DDP in the human nonsmall cancer cell line A549 was observed using Hoechst 33258/propidium iodide double staining.
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http://dx.doi.org/10.1055/s-0031-1296264DOI Listing
May 2010

Comparison of the surprising metal-ion-binding properties of 5- and 6-uracilmethylphosphonate (5Umpa2- and 6Umpa2-) in aqueous solution and crystal structures of the dimethyl and di(isopropyl) esters of H2(6Umpa).

Chemistry 2008 ;14(32):10036-46

Institute of Inorganic Chemistry, University of Zürich, 8057 Zürich, Switzerland.

5- and 6-Uracilmethylphosphonate (5Umpa(2-) and 6Umpa(2-)) as acyclic nucleotide analogues are in the focus of anticancer and antiviral research. Connected metabolic reactions involve metal ions; therefore, we determined the stability constants of M(Umpa) complexes (M(2+)=Mg(2+), Ca(2+), Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). However, the coordination chemistry of these Umpa species is also of interest in its own right, for example, the phosphonate-coordinated M(2+) interacts with (C4)O to form seven-membered chelates with 5Umpa(2-), thus leading to intramolecular equilibria between open (op) and closed (cl) isomers. No such interaction occurs with 6Umpa(2-). In both M(Umpa) series deprotonation of the uracil residue leads to the formation of M(Umpa-H)(-) complexes at higher pH values. Their stability was evaluated by taking into account the fact that the uracilate residue can bind metal ions to give M(2)(Umpa-H)(+) species. This has led to two further important insights: 1) In M(6Umpa-H)-cl the H(+) is released from (N1)H, giving rise to six-membered chelates (degrees of formation of ca. 90 to 99.9 % with Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). 2) In M(5Umpa-H)$-cl the (N3)H is deprotonated, leading to a higher stability of the seven-membered chelates involving (C4)O (even Mg(2+) and Ca(2+) chelates are formed up to approximately 50 %). In both instances the M(Umpa-H)-op species led to the formation of M(2)(Umpa-H)(+) complexes that have one M(2+) at the phosphonate and one at the (N3)(-) (plus carbonyl) site; this proves that nucleotides can bind metal ions independently at the phosphate and the nucleobase residues. X-ray structural analyses of 6Umpa derivatives show that in diesters the phosphonate group is turned away from the uracil residue, whereas in H(2)(6Umpa) the orientation is such that upon deprotonation in aqueous solution a strong hydrogen bond is formed between (N1)H and PO(3) (2-); replacement of the hydro gen with M(2+) gives the M(6Umpa-H)-cl chelates mentioned.
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http://dx.doi.org/10.1002/chem.200800998DOI Listing
February 2009

Cytotoxic activity and chemical reactivity of cis-platinum(II) and trans-palladium(II) complexes with diethyl (pyridinylmethyl)phosphates.

Eur J Med Chem 2009 Feb 27;44(2):660-4. Epub 2008 May 27.

Department of Bioinorganic Chemistry, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland.

A series of square-planar platinum(II) and palladium(II) complexes of the formula cis-[PtCl2L2] and trans-[PdCl2L2] [L stands for diethyl (pyridin-2-ylmethyl)phosphate (2-pmOpe) or diethyl (pyridin-3-ylmethyl)phosphate (3-pmOpe) or diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe)] have been synthesized and tested in vitro for their cytotoxicity against mouse leukemia L1210 cells. The results indicated that the cis-platinum complexes showed superior activity than trans-palladium complexes, but lower in comparison to cisplatin. The chemical reactivity of the tested complexes has been determined in an in vitro NBP test. The platinum complexes exhibited very high chemical reactivity in NBP test, higher than cisplatin. The results showed no correlation between cytotoxicity and chemical reactivity for platinum complexes. Two platinum(II) complexes {cis-[PtCl2(2-pmOpe)2], cis-[PtCl2(3-pmOpe)2]} have been synthesized and characterized by IR, 1H NMR, 31P NMR, and elemental analysis.
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http://dx.doi.org/10.1016/j.ejmech.2008.05.014DOI Listing
February 2009

trans-bis(3-aminoflavone-kappa2N,O)bis(perchlorato-kappaO)copper(II), a new potential antitumour agent.

Acta Crystallogr C 2007 Sep 17;63(Pt 9):m410-2. Epub 2007 Aug 17.

Department of Crystallography and Crystal Chemistry, University of Łódź, Pomorska 149/153, PL-90236 Łódź, Poland.

The title compound, trans-bis(3-amino-2-phenyl-4H-1-benzopyran-4-one-kappa(2)N,O(4))bis(perchlorato-kappaO)copper(II), [Cu(ClO4)2(C(15)H(11)NO(2))2], is composed of mononuclear units wherein the central Cu(II) cation occupies a crystallographic inversion centre. The cation is coordinated by two bidentate 3-aminoflavone ligands occupying the equatorial sites and by two perchlorate anions in the apical positions, thereby giving rise to a markedly elongated octahedral coordination geometry. Two symmetry-related intermolecular N-H...O hydrogen bonds link the molecules into chains of rings running parallel to the [100] direction, while intramolecular N-H...O hydrogen bonds help to determine the orientation of the apical perchlorate anions.
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http://dx.doi.org/10.1107/S010827010703747XDOI Listing
September 2007

Genotoxicity of novel trans-platinum(II) complex with diethyl (pyridin-4-ylmethyl)phosphate in human non-small cell lung cancer cells A549.

Chem Biol Interact 2007 Jun 7;168(2):135-42. Epub 2007 Apr 7.

Department of Cytogenetics and Plant Molecular Biology, University of Lodz, Banacha 12/16, Lodz, Poland.

The dynamic development of metal-containing anticancer drugs has started since the discovery of cis-diamminedichloroplatinum(II). For many years it was believed that trans platinum(II) compounds were non-active as antitumour agents because trans-diamminedichloroplatinum is biologically inactive although it binds to DNA and also forms monoadducts and cross-links. In the present work the ability of a novel platinum(II) compound trans-[PtCl(2)(4-pmOpe)(2)] to induce DNA damage in human non-small cell lung cancer cells A549 was examined using the alkaline comet assay. The obtained results revealed that the novel trans platinum(II) complex induced DNA strand breaks, which were effectively repaired during 2h of post-incubation, and cross-links which remained unrepaired under these test conditions. Apart from that, the modified comet assay with incubation with proteinase K was used to verify the ability of trans-[PtCl(2)(4-pmOpe)(2)] and cis-DDP to form DNA-protein cross-links. It has been proved that only trans-[PtCl(2)(4-pmOpe)(2)] complex exhibits the ability to induce DNA-protein cross-links. The results suggest a different mechanism of action of this compound in comparison to cis-DDP. It seems that trans geometry and the presence of two diethyl (pyridin-4-ylmethyl)phosphates as non-leaving ligands can determine dissimilar properties of the adducts formed on DNA and the different mechanism of action of trans-[PtCl(2)(4-pmOpe)(2)] and in consequence the efficacy in killing cancer cells.
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http://dx.doi.org/10.1016/j.cbi.2007.04.001DOI Listing
June 2007

Comparative studies on the mechanism of cytotoxic action of novel platinum II complexes with pyrazole ligands.

J Inorg Biochem 2006 Oct 23;100(10):1579-85. Epub 2006 May 23.

Department of Molecular Pharmacology, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.

In search for new platinum-based anticancer drugs, four cisplatin analogues, which contain pyrazole rings as non-leaving ligands, have been synthesized: cis-PtCl(2)(3,5-DM HMPz)(2), cis-PtCl(2)(Pz)(2), cis-PtCl(2)(ClMPz)(2), and cis-PtCl(2)(HMPz)(2), where Pz=pyrazole, H=hydroxyl, M=methyl. We tested their cytotoxicity, apoptosis induction ability, DNA damaging and modification properties comparing them in respect to the parent compound. The cytotoxic activity of these platinum pyrazole complexes toward the murine leukemia cell line was 2.9-3.8 times lower than actvity of cisplatin. The tested compounds varied in their mechanism of action by producing different DNA lesions. The most interesting compound seems to be the complex with chloromethyl groups at N1 of pyrazole rings, which exhibited the highest ability to form bifunctional adducts with DNA in vitro.
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http://dx.doi.org/10.1016/j.jinorgbio.2006.05.001DOI Listing
October 2006

Evaluation of P53 and BAX gene expression and induction of apoptosis and necrosis by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-diamminedichloroplatinum(II) (cis-DDP) in human lymphocytes.

Mutat Res 2006 Apr 27;604(1-2):28-35. Epub 2006 Jan 27.

Department of Cytogenetics and Plant Molecular Biology, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.

Currently cis-diamminedichloroplatinum(II) (cis-DDP) is one of the most commonly applied compounds in chemotherapy of many types of cancer. However, a drawback is that its effectiveness presents with many side effects. Therefore, human normal lymphocytes were chosen as a model system to study cis-bis(3-aminoflavone)dichloroplatinum(II) (the cis-Pt(II) complex of 3-aminoflavone) in comparison with cis-DDP. We examined the effect of both tested compounds on cell viability and induction of apoptosis and necrosis. Trypan blue and acridine orange/ethidium bromide staining were carried out, as well as quantitative analysis of the apoptotic signal of P53 and BAX induction caused by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. cis-DDP induced a decrease of cell viability and led to a higher increase in necrosis and apoptosis than did the cis-Pt(II) complex of 3-aminoflavone. Moreover, at the molecular level cis-DDP increased P53 and BAX expression in comparison with the other tested compound. The cis-Pt(II) complex of 3-aminoflavone showed a weaker genotoxic effect in normal lymphocytes in comparison with cis-DDP, which was a stronger inducer of apoptosis and necrosis.
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http://dx.doi.org/10.1016/j.mrgentox.2005.12.006DOI Listing
April 2006

Synthesis, spectroscopy and antiproliferative activity of cis- and trans-platinum(II) complexes with diethyl (pyridin-4-ylmethyl)phosphate. X-ray crystal structure of trans-Pt(II) complex.

J Inorg Biochem 2005 Oct;99(10):2024-31

Department of Bioinorganic Chemistry, Medical University, Muszyńskiego 1, 90-151 Łódź, Poland.

Preparations of cis- and trans-platinum(II) complexes of diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe) have been described. These complexes were identified and characterized by far-IR, 1H NMR, 13C NMR, 31P NMR and 195Pt NMR and microanalyses. The crystal and molecular structure of trans-platinum(II) complex i.e., trans-[PtCl2(4-pmOpe)2] was determined by the X-ray diffraction. Novel complexes were assayed for their potential antiproliferative effect against HT 29 (colorectal adenocarcinoma) and A 549 (non-small cell lung cancer) cell lines as well as normal human peripheral blood lymphocytes. The results obtained indicate that novel analogues of cis-diamminedichloroplatinum(II) cause inhibition of cells growth which suggest that they could be chemotherapeutic drugs in the future.
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http://dx.doi.org/10.1016/j.jinorgbio.2005.06.030DOI Listing
October 2005

Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP.

Invest New Drugs 2005 Aug;23(4):287-97

Department of Cytogenetics and Plant Molecular Biology, University of Lodz, ul. Banacha 12/16, 90-237 Lodz, Poland.

Lung cancer remains one of the most common causes of cancer-related death worldwide. Approximately 80% is histologically non-small cell lung carcinoma (NSCLC) and in about 70% of patients it is an unresectable type. Clinical studies indicated that application of platinum derivatives caused good results and combinations of platinum with other agents could improve median survivals. In view of the central problem of sufficient efficiency of drugs in chemotherapy, efforts have focused on the development of alternative platinum-based analogues that can be more effective in cancer treatment. cis-bis(3-aminoflavone)dichloroplatinum(II) (cis-Pt(II) complex of 3-aminoflavone) represents a novel class of platinum-based potential antitumour agents. In order to evaluate the degree of apoptosis, acridine orange/ethidium bromide and Hoechst 33258/propidum iodide double staining as well as RT-PCR (P53 and BAX expression evaluation) were used in lung cancer cell line A549 after treatment with this compound in comparison with cis-diamminedichloroplatinum(II) (cis-DDP). Apoptotic cells at early and late stages and also necrotic ones were observed after usage of cis-Pt(II) complex of 3-aminoflavone and the percentage of these cells outnumbered the values obtained after cis-DDP application. The former compound induced a higher percentage of P53 and BAX expression in A549 cells in comparison with the latter one. Results indicate the beneficial properties of cis-Pt(II) complex of 3-aminoflavone as a potential antitumor drug.
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http://dx.doi.org/10.1007/s10637-005-1437-zDOI Listing
August 2005

Electrochemical genosensing of the interaction between the potential chemotherapeutic agent, cis-bis(3-aminoflavone)dichloroplatinum(II) and DNA in comparison with cis-DDP.

J Pharm Biomed Anal 2005 Jul 17;38(4):645-52. Epub 2005 Mar 17.

Faculty of Pharmacy, Department of Analytical Chemistry, Ege University, Bornova, 35100 Izmir, Turkey.

The interaction of cis-diamminedichloroplatinum(II) (cis-DDP) and the potential novel chemotherapeutic agent, cis-bis(3-aminoflavone)dichloroplatinum(II) (cis-BAFDP) was studied electrochemically with calf thymus double-stranded DNA (dsDNA) by using differential pulse voltammetry (DPV) with disposable pencil graphite electrode (PGE) at the surface. These studies were prompted by beneficial biological properties of cis-BAFDP in comparison with cis-DDP, which were proven in vitro both in human normal and cancer cells and in vivo. The changes in the experimental parameters such as the concentration of cis-DDP and cis-BAFDP were studied by using DPV; in addition, the reproducibility of this genosensor and the detection limit for each compound were determined. After the interaction of cis-DDP with dsDNA, the DPV signal of guanine and adenine was found to be decreasing. In comparison with cis-DDP, a dramatic decrease at adenine signal was also obtained after the interaction of cis-BAFDP and dsDNA. Similar results were also found in solution phase after the latter compound interacts with poly[A]. The features of the proposed electrochemical method for the detection of cis-BAFDP with DNA in comparison with cis-DDP are discussed and compared with those methods previously reported for the other type of DNA-targeted agents in the literature.
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http://dx.doi.org/10.1016/j.jpba.2005.02.010DOI Listing
July 2005

Ethyl (2-pyridylmethyl)phosphonate.

Acta Crystallogr C 2005 Jan 11;61(Pt 1):o4-6. Epub 2004 Dec 11.

Department of Crystallography and Crystal Chemistry, University of Łódź, Pomorska 149/153, 90-236 Łódź, Poland.

Molecules of the title compound, C8H12NO3P, exist as zwitterions. The positive charge formally located on the N atom is spread over the pyridyl ring. A partial delocalization of negative charge within the O-P-O system is observed. The conformational features and hydrogen-bonding network of the title compound are compared with the structure of (2-pyridylmethyl)phosphonic acid.
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http://dx.doi.org/10.1107/S0108270104029221DOI Listing
January 2005

Induction of apoptosis and necrosis in A549 cells by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP.

Mutat Res 2004 Sep;563(1):61-70

Department of Cytogenetics and Plant Molecular Biology, University of Lodz, ul. Banacha 12/16, 90-237, Poland.

Non-small cell lung cancer (NSCLC) includes a group of tumors that respond poorly to drugs. cis-Diamminedichloroplatinum(II) (cis-DDP) toxicity still remains problematic, and not completely solved by the improvement of supportive care. Therefore, the cis-Pt(II) complex of 3-aminoflavone was selected from cis-DDP analogues with a more favourable toxic profile towards normal cells and at least similar or better anti-tumor activity in comparison with cis-DDP. The aim of this research is to compare the ability of the cis-Pt(II) complex of 3-aminoflavone and cis-DDP to induce apoptosis and necrosis in the human non-small cancer cell line A549. Trypan blue dye exclusion, fluorochrome staining (acridine orange/ethidium bromide double staining), MTT and TUNEL (TdT-mediated dUTP Nick-End Labeling) assays were used. The results obtained show that the cis-Pt(II) complex of 3-aminoflavone is more active in inducing apoptosis and necrosis and in decreasing viability in A549 cells than cis-DDP, which suggests that it could be a potential chemotherapeutic drug.
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http://dx.doi.org/10.1016/j.mrgentox.2004.05.018DOI Listing
September 2004