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Macrocyclic complexes as models for copper(II) bonding in cupredoxins: Proof of concept
Ulrichová, Tereza ; Hermann, Petr (advisor) ; Hudeček, Jiří (referee)
Currently, modified electron transport metaloproteins with presence ion Cu(II) in their active site are most commonly used to study kinetics of electron transfer. One of the most studied model protein is cupredoxin azurin from P. aeruginosa with standard redox potential approximately 310-360 nm (depends on experimental conditions and techniques). Ion Cu(II) in azurin is coordinated by the side chain atoms of His46 , His117 , Cys112 , Met121 and carbonyl of Gly45 . The aim of this work was to prepare macrocyclic ligand, 1-[1H-imidazol-2- yl)methyl]-1,4,7-triazacycklononanu (LIM ), which would be able to form stable complexes with both of copper ions Cu(II) and Cu(I). Such as macrocyclic complexes could be utilized as low molecular models of active sites in proteins. The ligand was prepared using five-step synthesis employing protection of macrocycle, reduction and subsequent bromation of 1H- imidazol-2-karbaldehyd, and following alkylation reaction. Deprotection of macrocycle revealed final product of ligand. All reaction intermediates and prepared ligand were characterized by NMR and MS. Potentiometric titrations determined ligand protonation constant (log K1 = 10,62, log K2 = 6,65, log K3 = 4,91), which describe acid-base properties of a ligand in an aqueous solution. Similarly, the coordination...
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Complexes of cyclen-based macrocyclic ligands with a phosphinate pendant arm
Urbanovský, Peter ; Hermann, Petr (advisor) ; Lyčka, Antonín (referee) ; Pinkas, Jiří (referee)
Lanthanide(III) complexes of DOTA derivatives are utilized in the medical imaging techniques such as magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS), nuclear imaging (PET and SPECT), or optical methods (luminescence). It has been shown that relaxometric parameters of the Gd(III) complexes of DOTA derivatives with a phosphinic acid pendant arm (Gd-DO3APR ) can reach optimal values (e.g. water residence time, τM, being close to ~10 ns). The relaxometric parameters can be further modified through the phosphorus substituents. It is also known that the complexes possess a high thermodynamic stability and they are kinetically inert. The main goal of this Thesis is an investigation of the effect of pendant amino group protonation in substituents bound to the phosphorus atom on properties of the complexes. Thus in this Thesis, DOTA derivatives with the phosphinic acid pendant arm with an amino group and their complexes were prepared and characterized. The complexes are intended as contrast agents for molecular imaging techniques (mainly for MRI and 31 P MRS). The first part of the Thesis introduces two new versatile "phospha-Mannich" protocols performed under mild conditions. Amino-H-phosphinic acids (AHPAs) were synthesized with excess of...
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Lanthanide complexes of DOTA-"trans"-diamide
Obuch, Jakub ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Macrocyclic complexes are of great interest due to their utilization in many medic- inal applications, such as MRI contrast agents and radiopharmaceuticals. These com- plexes overcome the toxicity of free heavy metal ions and, thus, enable their use in vivo. In this Thesis, diamide derivative of DOTA (tDODAM) and its lanthanide(III) complexes were prepared and characterised in solution and in the solid state. For cerium(III) com- plex, formation and dissociation kinetics were studied. Structure and dynamics of eu- ropium(III) complex were investigated by multinuclear NMR spectroscopy and various 2D NMR techniques. Similarly to Ln(III)-DOTA complexes, the complexes form square- antiprismatic (SA) and twisted-square-antiprismatic (TSA) isomers and their ratio in solution was determined across the lanthanide series. Structures of 7 lanthanide(III) complexes in the solid state were determined. Thermodynamic data were obtained for Cu(II), Zn(II), Pb(II), Ce(III), Eu(III) and Lu(III) complexes by potentiometric titration. 1
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17O NMR study of LnIIIcomplexes of H4do3apOEt ligand
Svítok, Adam ; Hermann, Petr (advisor) ; Dračínský, Martin (referee)
Macrocyclic complexes of H4dota-like ligands are used in various fields, mainly in medicine. e. g. as MRI contrast agents or luminescent probes. Their applications are greatly influenced by stereochemistry. Stereoisomers of these complexes mostly interconvert with each other in solution. This interconversion can be studied by NMR spectroscopy This work is intended to test 17 O NMR spectroscopy as a tool for monitoring dynamic processes where phosphonate group in the complexes of methylphosphonate derivatives of H4dota is involved. To this end, ligand H4do3apOEt and his LnIII -complexes (Ln ≠ Pm) containing 17 O-labeled phosphonate group were synthesized. Next, 17 O NMR spectra of these complexes were measured and analysed. In an analogy with H4dota complexes, signals of both non-coordinated and coordinated oxygen atoms (except GdIII ) in the complexes could be detected. Fraction of TSA (twisted square-antiprism) and SA (square-antiprism) isomers was determined from the acquired 17 O NMR spectrum for each complex. The determined values were compared with those obtained by analysing 1 H and 31 P NMR spectra of the complexes, which were also measured. The TbIII , DyIII and YbIII complexes (because of high resolution of their 17 O NMR spectra) and CeIII complex (because of anomalous properties of its...
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Complexes of macrocyclic ligands
Buziková, Michaela ; Hermann, Petr (advisor) ; Vojtíšek, Pavel (referee)
Macrocyclic ligands are compounds well-known and studied for their ability to bind metal ions into complexes possessing high kinetic inertness and thermodynamic stability. These properties make such compounds useful in medicine. This thesis focuses on ligand cis- DO2A2P, which belongs to a series of ligands based on cyclen skeleton with mixed acetate and phosphonate pendant arms. A lot of attention has been paid to the other members of this ligands series, but the information about cis-DO2A2P is still incomplete. In this thesis, the complexation properties of mentioned ligand were studied, as well as properties of its complexes with the lanthanide ions in solution. Key words Macrocycles; polydentate ligands; lanthanides; transition metals; organophosphorus acids
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Polycyclic tetraazamacrocycles
Plutnar, Jan ; Hermann, Petr (advisor) ; Podlaha, Jaroslav (referee) ; Růžička, Aleš (referee)
Two series of new bicyclic tetraazamacrorycles built up on skeletons of either 1,5,8,12-tetraazabiryclo[10.2.2]hexadecane (1,4-en-cyclam) I or 1,4,8,11- tetraazabicyclo[6.6.2]hexadecane (1,8-en-ryclam) 8 were prepared. The 1,4- en.cyc|am-based unsymmetrica| compounds bearing the pnitrobenzy| moieý (precursor for a biomolecule-conjugation) were synthesised exploiting the low so|ubi|iý of the intermediate quaternary derivative 2 in non-po|ar so|vents. The |igands 3 and 6 exhibited the expeďed comp|exing abi|ity towards copper(Il) and zinc(Il) although the complexation proceeded relatively slowly (at room temperature in order of hours). The mďa| comp|exes thus formed exhibited thermodynamic stability constants lower than those repofted for similar monoryclic tetraazamacrocycles (cyclam, Me+cyclam) probably due to inadvisability of the conformational change (chair or twisted-boat -> boat conformation of the piperazine subunit) conneďed to the metaI ion encapsulation. On the other hand, when the stability of coppe(Il) complex of 3 is compared to stabi|iý constant reported for the biryc|ic amine 1, the trend in the values of these constants is the same for the couple ligand I - ligand 3 as for the couple cyclam - Me+cyclam. During the attempted synthesis of the monoacetate ligand 5a an unusual reaction behaviour...
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Dynamics of paramagnetic complexes observed by Nuclear Magnetic Resonance
Blahut, Jan ; Hermann, Petr (advisor) ; Botta, Mauro (referee) ; Dračínský, Martin (referee)
In this Thesis, structure and dynamics of paramagnetic complexes for medical application are studied by Nuclear Magnetic Resonance (NMR). It focuses mainly on development of contrast agents (CA) for Magnetic Resonance Imaging (MRI) which is one of the most effective radiodiagnostic method nowadays. Most of the MRI CAs contains paramagnetic complexes of d- and f-metal ions. The presence of unpaired electron in proximity of NMR active nuclei has two main effects: paramagnetically induced shift and paramagnetically induced relaxa- tion. Both processes can dramatically change the NMR spectrum and often make it unobservable at all. Nevertheless, in many cases, acquisition of such spectra is possible and sometimes even less time-consuming than observation of diamag- netic molecules. Enhanced T1 relaxation allows faster pulse sequence repetition and increased chemical shift dispersion may lead to resolution of originally over- lapped signals. Moreover, the analysis of paramagnetic effects can provide useful information about the structure and dynamics of the studied system. Theoretical background of these effects is described in the Introduction of the Thesis. In the first part of Discussion in the Thesis, a new class of contrast agents for 19F-MRI based on nickel(II) and cobalt(II/III) ions is introduced...
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