Search for promising luminophores and antitumor agents in a series of mixed ligand complexes of rare-earth and endogenous metals based on polypyridine,phosphine ligands and tetrazole derivatives
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Synthesis of coordination compounds of rare-earth elements is a widely developing field due to the attractive luminescent properties of these metal complexes.The Ln(III)complexes demonstrate long lifetimes of excited states and large quantum yields;narrow bands in the visible and infrared spectral ranges are observed in the emission spectrum.Due to the good physical parameters that are key in describing the luminescence of the compounds,these complexes are promising luminescent materials for organic light emitting diodes(OLED)and bioimaging.The increased interest in the use of luminescent complexes for the study of cellular structures and intracellular processes indicates the effectiveness and potential of such compounds in bioimaging.To date,fluorescence microscopy has mainly used organic fluorophores(small fluorescent molecules or fluorescently labeled antibodies)to visualize cells,that possess certain limitations.Metal complexes have significant advantages over their organic counterparts,including long emission times,resistance to photobleaching,and the ability to easily modify the ligand environment to target specific organelles,signaling pathways and individual molecules within cells.Therefore,the search and development of new rare-earth luminophores is an important task.
The aim of the project is to synthesize new mixed ligand complexes of endogenous metals(copper(II),zinc(II),cobalt(II)and others)and rare earth metals with different classes of organic ligands(derivatives of tetrazole,polypyridine and phenylphosphine)in order to obtain cytotoxic and luminescent compounds.The structure,stability in solution,as well as other physicochemical properties of the obtained coordination compounds will be studied using mass,NMR and IR spectroscopy,X-ray diffraction and powder X-ray analysis.For a number of synthesized compounds,the luminescent properties will be studied.In addition,the cytotoxic activity of the complexes on 2D and 3D cell culture models,the effect of the compounds on the functional activity of P-glycoprotein,the interaction with DNA will be studied.As a final part of the project in vivo studies will be conducted.In accordance with the obtained results on luminescence and biological activity,new complexes of lanthanides will be considered as potential materials for bioimaging.
Expected results:1)Methods for the synthesis and isolation of a series of mixed ligand complexes of endogenous and rare earth metals with derivatives of tetrazole,polypyridine and phenylphosphine will be developed.The halide,acetate,and nitrate ions will be used as anions for the synthesis of the complexes.
2)We will use a combination of different physicochemical research methods to identify and characterize the obtained compounds:elemental analysis(CHNS;metal analysis by complexometry),single crystal X-ray diffraction,powder X-ray diffraction,differential scanning calorimetry(DSC),thermogravimetric analysis,and electronic(diffuse reflectance spectroscopy),IR,and NMR spectroscopy.
3)The physicochemical properties of the obtained complexes will be studied.In particular,solubility and stability in physiological like media will be investigated by electron spectroscopy and mass spectrometry.
4)Luminescent properties will be studied for lanthanide compounds and organic ligands.For polycrystalline substances,absorption,luminescence and emission spectra will be obtained,as well as data on the lifetimes of excited states and quantum yields.Emission of lanthanide compounds occurs upon indirect excitation("antenna effect"),i.e.first,the energy is absorbed by the ligand molecules,after which energy is transferred to the metal ion,followed by emission characteristic of the metal ion.Therefore,the study of the luminescent properties of organic ligands is an important part of our work,as well as the study of the luminescence of the obtained lanthanide compounds.
5)In the laboratory conditions,the cytotoxic properties of the complexes and ligands against human tumor cell lines(Hep2-laryngeal carcinoma,MCF-7-breast carcinoma)will be studied using the IN Cell Analyzer 2200(GE Healthcare,UK),which allows conducting high content screening.The toxicity of the complexes that showed the highest effect on a monolayered two-dimensional model will be studied using 3D cell models.The half-maximum inhibition value IC50,which is the concentration of the drug at which 50%of the cells die,will be calculated.This will allow us to compare our results on the used cell lines with literature data and estimate the therapeutic potential of the complexes obtained during this project.
6)The selected compounds will be tested for belonging to the substrates,inhibitors,and inducers of the glycoprotein-P transporter protein encoded by the MDR(multidrug resistance gene)genes involved in drug resistance development mechanisms.To understand the mechanism of action for a number of complexes,we will study the interaction with DNA,the main target of antitumor drugs.For the most promising compounds,the in vivo effects on laboratory animals will be studied.
7)Based on the results of the work,generalizing patterns of structure-activity will be analyzed and recommendations will be developed on the future use of advanced metal complexes for the development of new drugs and the creation of OLED devices,as well as their use in bio-visualization.
8)Based on the research results,it is supposed to publish a number of articles in foreign journals and abstracts in materials of Russian and international conferences.
Synthesis of coordination compounds of rare-earth elements is a widely developing field due to the attractive luminescent properties of these metal complexes.The Ln(III)complexes demonstrate long lifetimes of excited states and large quantum yields;narrow bands in the visible and infrared spectral ranges are observed in the emission spectrum.Due to the good physical parameters that are key in describing the luminescence of the compounds,these complexes are promising luminescent materials for organic light emitting diodes(OLED)and bioimaging.The increased interest in the use of luminescent complexes for the study of cellular structures and intracellular processes indicates the effectiveness and potential of such compounds in bioimaging.To date,fluorescence microscopy has mainly used organic fluorophores(small fluorescent molecules or fluorescently labeled antibodies)to visualize cells,that possess certain limitations.Metal complexes have significant advantages over their organic counterparts,including long emission times,resistance to photobleaching,and the ability to easily modify the ligand environment to target specific organelles,signaling pathways and individual molecules within cells.Therefore,the search and development of new rare-earth luminophores is an important task.
The aim of the project is to synthesize new mixed ligand complexes of endogenous metals(copper(II),zinc(II),cobalt(II)and others)and rare earth metals with different classes of organic ligands(derivatives of tetrazole,polypyridine and phenylphosphine)in order to obtain cytotoxic and luminescent compounds.The structure,stability in solution,as well as other physicochemical properties of the obtained coordination compounds will be studied using mass,NMR and IR spectroscopy,X-ray diffraction and powder X-ray analysis.For a number of synthesized compounds,the luminescent properties will be studied.In addition,the cytotoxic activity of the complexes on 2D and 3D cell culture models,the effect of the compounds on the functional activity of P-glycoprotein,the interaction with DNA will be studied.As a final part of the project in vivo studies will be conducted.In accordance with the obtained results on luminescence and biological activity,new complexes of lanthanides will be considered as potential materials for bioimaging.
Expected results:1)Methods for the synthesis and isolation of a series of mixed ligand complexes of endogenous and rare earth metals with derivatives of tetrazole,polypyridine and phenylphosphine will be developed.The halide,acetate,and nitrate ions will be used as anions for the synthesis of the complexes.
2)We will use a combination of different physicochemical research methods to identify and characterize the obtained compounds:elemental analysis(CHNS;metal analysis by complexometry),single crystal X-ray diffraction,powder X-ray diffraction,differential scanning calorimetry(DSC),thermogravimetric analysis,and electronic(diffuse reflectance spectroscopy),IR,and NMR spectroscopy.
3)The physicochemical properties of the obtained complexes will be studied.In particular,solubility and stability in physiological like media will be investigated by electron spectroscopy and mass spectrometry.
4)Luminescent properties will be studied for lanthanide compounds and organic ligands.For polycrystalline substances,absorption,luminescence and emission spectra will be obtained,as well as data on the lifetimes of excited states and quantum yields.Emission of lanthanide compounds occurs upon indirect excitation("antenna effect"),i.e.first,the energy is absorbed by the ligand molecules,after which energy is transferred to the metal ion,followed by emission characteristic of the metal ion.Therefore,the study of the luminescent properties of organic ligands is an important part of our work,as well as the study of the luminescence of the obtained lanthanide compounds.
5)In the laboratory conditions,the cytotoxic properties of the complexes and ligands against human tumor cell lines(Hep2-laryngeal carcinoma,MCF-7-breast carcinoma)will be studied using the IN Cell Analyzer 2200(GE Healthcare,UK),which allows conducting high content screening.The toxicity of the complexes that showed the highest effect on a monolayered two-dimensional model will be studied using 3D cell models.The half-maximum inhibition value IC50,which is the concentration of the drug at which 50%of the cells die,will be calculated.This will allow us to compare our results on the used cell lines with literature data and estimate the therapeutic potential of the complexes obtained during this project.
6)The selected compounds will be tested for belonging to the substrates,inhibitors,and inducers of the glycoprotein-P transporter protein encoded by the MDR(multidrug resistance gene)genes involved in drug resistance development mechanisms.To understand the mechanism of action for a number of complexes,we will study the interaction with DNA,the main target of antitumor drugs.For the most promising compounds,the in vivo effects on laboratory animals will be studied.
7)Based on the results of the work,generalizing patterns of structure-activity will be analyzed and recommendations will be developed on the future use of advanced metal complexes for the development of new drugs and the creation of OLED devices,as well as their use in bio-visualization.
8)Based on the research results,it is supposed to publish a number of articles in foreign journals and abstracts in materials of Russian and international conferences.