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Coordination chemistry of pharmaceuticals
Malová, Zuzana ; Lukeš, Ivan (advisor) ; Vojtíšek, Pavel (referee)
Present methods for diagnosis of neurodegenerative diseases are rather limited and in clinical practise are missing. This thesis is focused on utilization of the positron emission tomography using isotope 64 Cu(II). For the project, two contrast agents were proposed containing ligand for Cu (II) coordination and thioflavine T derivative as fluorescent dye, also as a targeting compound. Structure of the thioflavine T derivative was defined by X-ray structural analysis. The selected fluorescent dye has a high affinity for incipient amyloids and, when bound to their structure, has enhanced fluorescent properties. The proposed ligands are tetraazacyclic. The first one is a diamide, where the thioflavin T derivative is part of a macrocyclic ring. The second selected ligand is linked to the thioflavin T derivative via a linker. Key words: complexes; pharmaceuticals; transition metals
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Coordination chemistry of pharmaceuticals
Malová, Zuzana ; Lukeš, Ivan (advisor) ; Vojtíšek, Pavel (referee)
Present methods for diagnosis of neurodegenerative diseases are rather limited and in clinical practise are missing. This thesis is focused on utilization of the positron emission tomography using isotope 64 Cu(II). For the project, two contrast agents were proposed containing ligand for Cu (II) coordination and thioflavine T derivative as fluorescent dye, also as a targeting compound. Structure of the thioflavine T derivative was defined by X-ray structural analysis. The selected fluorescent dye has a high affinity for incipient amyloids and, when bound to their structure, has enhanced fluorescent properties. The proposed ligands are tetraazacyclic. The first one is a diamide, where the thioflavin T derivative is part of a macrocyclic ring. The second selected ligand is linked to the thioflavin T derivative via a linker. Key words: complexes; pharmaceuticals; transition metals
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Ligands for Multifunctional Dinuclear Complexes
Králová, Marie ; Vojtíšek, Pavel (advisor) ; Lukeš, Ivan (referee)
Title: Ligands for Multifunctional Dinuclear Complexes Author: Marie Králová Site: Charles University in Prague, Faculty of Science Supervisor: doc. RNDr. Pavel Vojtíšek, CSc. Abstract The aim of this work was to prepare substitued phenols as ligands for binuclear complexes of copper(II), which could be used as anion receptors. Two main sythethic strategies are summarised in the introduction: First is single step Mannich-type reaction of 4-substitued phenol, paraformaldehyde and secondary amine, other includes preparation of substitued bis(halomethy)phenol and it's following reaction with secondary anime. A single step Mannich-type reaction was used for preparations of following known ligands: 2,6-bis[(N-methyl piperazine-1-yl)methyl]-4-formyl phenol (L1), 2,6-bis[(N- methyl piperazine-1-yl)methyl]-4-nitro phenol (L3) and 2,6-bis[(N-phenyl piperazine-1- yl)methyl]-4-nitro phenol (L4). The new ligand, 2,6-bis[(N-phenyl piperazine-1-yl)methyl]- 4-formyl phenol (L2), was prepared in the same way. A structure of this ligand was determined using X-ray. One Pd(II) complex [PdL2Cl2]·1.5MeCN (K3) was prepared and it's structure was determined. UV-VIS spectroscopy was used to study interactions in ligand - metal and ligand - metal - anion systems in order to determine the anion - binding capabilities of the...
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Prion Diseases - a role of transition metal ions
Malová, Zuzana ; Lukeš, Ivan (advisor) ; Moško, Tibor (referee)
Prion diseases are widely spread diseases among mammalians. They are characterized by a change of prion protein structure PrPC (cellular, native state) to PrPSc (scrapie, structure typical for prion diseases). It is a change at secondary structure of protein from α-helical to β-sheet structure, which aggregates in brain. One possibility, why it happens is higher transitional metal ions concentration (Zn(II), Cu(II), Fe(III)) in the brain, which bind to PrPC and affects its structure. Aim of this thesis is a synthesis one of protentional drugs based on 2-aminothiazole and its modification to bind fluorescent or radiochemical markers and in future study of its possible interaction with transition metal ions. Key words: complexes; macrocyclic ligands; copper; prion diseases
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From Monomeric to Dendrimeric MRI Contrast Agents
Rudovský, Jakub ; Lukeš, Ivan (advisor) ; Botta, Mauro (referee) ; Peters, Joop (referee)
4, Conclueione To conclude, in my Thesis I found that ligands with phosphorus acid ped- a]11 alm substituting carboxylate in DOTA structure are endowéd with several Íavor- able features like a water residence liťetime optimal for a preparation of high- relaxivity covalent conjugates' Importantly, these promising p'óp.'ti.. were proved to persist even after the conjugation as was demonstrated ón u iy.."t.ical áitopic model compound for the first time. Imporlantly, the folrowing study of row- ge.nelatlon PAMAM conjugate proved that, unlike most oťthe published studies, trre rela:livity of these macromolecular systems ísnot exchang.-li.it"d. This has al. lowed meto investigate in detaíl the limiting effects on the iela;rivity of the internal ro^tation of the complex in the conjugates. In addition' I shown that tňe local mottons ofthe dendrimer backbone and ofthe conjugated complexes can be slowed down by a- formatíon of supramolecular adducts with cationic polyaminoacids. Also, I was able to quantitatively evaluate the effects of the local motíons and to effectively reduce them. As a result, the efficacy of these systems as relaxation agents is the highest so far reported for this class of compounds that can find a varieň of poten- tial biomedical/bioinorganic applications. For the close future, we plan in...
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Geminal bis(phosphinates)
David, Tomáš ; Lukeš, Ivan (advisor) ; Grüner, Bohumír (referee) ; Růžička, Aleš (referee)
Slow complexation is one of the major limitations of current macrocyclic chela- tors utilized in nuclear medicine for complexation of metal radionuclides. This property can be improved by ligand design. Among metal radioisotopes, the copper ones (e.g. 60Cu, 61Cu, 62Cu, 64Cu and 67Cu) have become commonly available in recent years and cyclam-derived ligands are the most suitable ligands for Cu2+ complexation. To alter the complexation rate, bis(phosphinic acid) group is promising unit as it is able to complex metal ions in acidic solu- tions. However, geminal bis(phosphinates) represent poorly studied group of compounds and, thus, it is challenging to uncover their properties. Several simple amino-bis(phosphinates) were synthesized and its acid-base and coordi- nation properties were studied. Unlike structurally similar geminal bis(phosphonates), the title compounds showed negligible adsorption onto hydroxyapatite (commonly used model of bone tissue). The obtained knowledge dealing with geminal bis(phosphinates) was utilized in synthe- sis of two novel cyclam derivatives. The ligands (bearing either one geminal bis(phosphinate) or one geminal phosphino-phosphonate pendant arm) were synthesized by highly efficient procedure. The corresponding Cu2+ complexes are formed with very high rates and show...
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Potential contrast agents for MRI based on manganese(II) complexes
Drahoš, Bohuslav ; Lukeš, Ivan (advisor) ; Geraldes, Carlos F. G. C. (referee) ; Toth, Imre (referee)
The thesis is focused on the synthesis and characterization of novel Mn2+ complexes as alternative to Gd3+ chelates which are wide-spread contrast agents in Magnetic Resonance Imaging (MRI). In the perspective to find suitable chelators of Mn2+ , three groups of pentadentate ligands with different size of macrocylic cavity, different donor atoms and number of pendant arms containing various functional groups have been investigated. Coordination numbers of 6 or 7 were found in the crystal structure of the Mn2+ complexes enabling binding of one or two water molecules in the first coordination sphere. The direct water coordination causes a decrease in the complex stability and thus, the thermodynamic stability of investigated chelates is lower than that of polyaminocarboxylate complexes and their dissociation is very fast in comparison to [Mn(nota)] and [Mn(dota)]2- . The studied Mn2+ complexes do not undergo oxidation in air except for complexes with 12-membered ligands which are oxidized to Mn3+ species. The proton relaxivities of the bishydrated complexes are two times higher than those for monohydrated complexes and are comparable to those of commercial contrast agents based on Gd3+ complexes. Variable-temperature 17 O NMR data revealed that the water exchange varies from slow to intermediate or...
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Titaniun Dioxide - Phosphonate Assemblies as Medical Nanoprobes
Řehoř, Ivan ; Lukeš, Ivan (advisor) ; Lang, Kamil (referee) ; Peters, Joop (referee)
Titanium Dioxide - Phosphonate Assemblies as Medical Nanoprobes Ivan Řehoř PhD. Thesis Abstract: Multimodal imaging-therapeutic nanoprobe TiO2@RhdGd was prepared and successfully used for in- vitro and in-vivo cell tracking as well as for killing of cancer cells in-vitro. TiO2 nanoparticles, 12 nm in diameter, were used as a core for phosphonic acid modified functionalities, responsible for contrast in MRI and optical imaging. The phosphonic acid derivatives, used for surface modification, allows for grafting extraordinarily high loads of irreversibly adsorbed molecules of both types in one step. The prepared probe shows very high 1 H r1 relaxivity value as well as relaxivity density value, both crucial parameters for its use in MRI. The presence of fluorescent dye in its structure allows for its visualization by means of fluorescence microscopy. The applicability of the probe was studied, using three living systems - mesenchymal stem cells, cancer HeLa cells and T-lymphocytes. The probe did not exhibit toxicity in any of these systems and its long time storage in a lysosomal compartment was confirmed. Labeled cells were successfully visualized in-vitro by means of fluorescence microscopy and MRI. Consequent visualization of labeled cells in-vivo by means of fluorescence microscopy was also achieved....
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