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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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Macrocyclic ligands and their complexes with metal ions for utilization in imaging methods
Hrček, Martin ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Currently, a number of methods, both diagnostic and therapeutic, find use in the field of nuclear medicine. The importance of macrocyclic ligands, capable of coordination of ions of employed metal radionuclides, is rising for both mentioned areas. Great potential lies in the area of the so-called theragnostics, i.e., drugs with both diagnostic and therapeutic functions. This thesis makes the first steps towards the concept of a theranostic ligand containing two macrocyclic coordinating centres, each individually optimised for coordinating radioisotopes of one metal ion. The coordination of Ga(III), currently used in diagnostics, is provided in the studied model system by a nine-membered macrocycle with phosphinate pendant arms. The coordination of Lu(III), currently used for radiotherapy, is provided by a twelve-membered macrocycle with phosphinate pendant arms. The results of the NMR measurements in this thesis show that the studied model system behaves in agreement with requirements placed upon the conceived drug. A macrocyclic ligand L1e, optimised for coordination of Lu(III), was prepared with the intended use in the synthesis of the proposed drug. H-phosphinic acids and a derivative of cyclene were also prepared as precursor compounds for a series of bifunctional ligands L1a - L1e. Keywords...
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Synthesis of phosphono-bis(phosphinate) cyclam derivative
Chrappa, Michal ; Hermann, Petr (advisor) ; Veselý, Jan (referee)
Radiopharmaceuticals containing copper isotopes can be used as diagnostic tools (methods PET, SPECT) or agents for tumour treatment. Copper radionuclides must be applied into the organism in the form of a coordination compound with suitable ligand. Derivatives of 1,4,8,11-tetraazacyclotetradecane (cyclam) are some of the most suitable ligands for Cu (II). A coordination compound must be thermodynamically stable and kinetically inert, the ligand must coordinate the metal ion as quickly as possible. In this Diploma thesis, one of the first unsymmetrically substituted derivatives of cyclam has been synthesized using two methods of orthogonal protection. The synthesized ligand contains one phosphonate and one methylene bis(phosphinate) pendant arm. Copper complex of the ligand was prepared, and its acid assisted dissociation kinetics were studied.
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Macrocycles and complexation of large metal cations
Faltejsek, Jan ; Hermann, Petr (advisor) ; Drahoš, Bohuslav (referee)
In the last years, radioisotopes of heavy elements from the bottom of the Periodic Table have been increasingly used in nuclear medicine with focus on alpha-therapy. These large metal ions demand ligands fulfilling their special requirements. Complexes of polyazamacrocyclic ligands have been used in radiomedicine for a long time as diagnostic and therapeutic agents. This work aims to con- tribute to understanding of coordination chemistry of large macrocycles toward large metal ions. Thus, this work deals with structural studies, formation and decomplexation kinetics of Ln(III)-H4pyta complexes employing X-ray solid-state and solution NMR/UV-Vis spectroscopic data. The H4pyta is a 18-membered hexaazamacrocycle formed by two pyridine units and four amine groups which are modified with four acetate pendant arms. In the solid state, several isomeric complexes were structu- rally characterized. Large Ln(III) ions form decacoordinated species with two and two acetates on each side of the macrocyclic N6-plane. Small Ln(III) binds the ligand in a nonadentate fashion with one pendant non-coordinated. In the middle of lanthanide series, both isomers were characterized for several Ln(III) ions. Formation of the complexes takes place in a three-step mechanism with fast formation of an out-of-cage intermediate...
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MRI contrast agents for modern applications
Kotková, Zuzana ; Hermann, Petr (advisor) ; Pinkas, Jiří (referee) ; Drahoš, Bohuslav (referee)
Zuzana Kotková - Ph.D. Thesis: MRI Contrast Agents for Modern Applications 1 Abstract Over the last few decades, Magnetic Resonance Imaging (MRI) has become one of the most powerful medicinal methods for the diagnosis of various diseases (Fig. A1a ). In several types of examinations, contrast agents (CAs) are used to increase the quality of images (Fig. A1b ). These contrast agents are usually based on paramagnetic metal complexes of macrocyclic ligands. In dependence on the measured nuclei, two basic groups of CAs are considered - 1 H MRI CAs and, recently, also 19 F "hot-spot" CAs. The 1 H MRI CAs are based on Gd3+ complexes of macrocyclic ligands with one water molecule coordinated to the central metal ion (Fig. A1c ) and the effect of the CAs is to shorten the relaxation times of water protons. (a) (b) (c) Fig. A1: Illustrative pictures for Magnetic Resonance Imaging (MRI) method; (a) whole body MRI tomograph,* (b) an example of MR head scans with the use of MRI CA** and (c) schematic general structure of a contrast agent based on Gd3+ complex of macrocyclic ligands (for more details see the Thesis, section 1.3.3, Fig. 18). * https://www.ottawaheart.ca/test-procedure/cardiac-mri (Accessed 25 Febr. 2023) ** https://affordablemri.com/mri-explained (Accessed 25 Febr. 2023) The shortening of relaxation...
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Selective protection of pentaerythrityltetraamine
Mangl, Ondřej ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Selective protection of functional groups is a commonly used method which is used in multistep synthesis. Pentaerythrityltetraamine (PEA) is substance with four amino groups and substances with one to three selectively protected amino groups were prepared. Protections by t-butyloxycarbonyl (Boc) which is stable under neutral and basic conditions and can be deprotected in the acidic conditions, and with benzyloxycarbonyl (Cbz) which is stable under acidic and basic conditions and can be eliminated by hydrogenation was tested. Separation and purification of the protected amines was done by chromatography. Selectively protected PEA can be also prepared by indirect path by stepwise reduction of pentaerythrityltetraazide. Pentaerythritylmonoamine-triazide is prepared two-phase reduction and the amino group of the monoamine is protected with Boc or Cbz.
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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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Pyridine-N-oxide analogue of DOTA as a building block for MRI contrast agents
Polášek, Miloslav ; Hermann, Petr (advisor) ; Geraldes, Carlos F. G. C. (referee) ; Botta, Mauro (referee) ; Marek, Radek (referee)
Conclusions In my PhD project I synthesized two new polydentate macrocyclic ligands, the monofunctional DO3A-pyNO and the bifunctional DO3A-pyNO-C. Both compounds are based on the design of DOTA, with one of the acetate pendant arms being replaced with a pyridine-Noxide arm. This structural modification has a tremendous influence on chemical properties of the lanthanide(III) complexes of these compounds. The water exchange rate in the gadolinium(III) complexes is significantly accelerated in comparison with the complexes of DOTA. In fact, the values are almost optimal for use of the Gd(III) complexes as contrast agents for magnetic resonance imaging. Besides, the complexes exist exclusively in the form of square antiprismatic isomers. I investigated the complexes by various physico-chemical techniques in solution and in solid state, in order to elucidate the relationship between their structure and properties. On the basis of these results I found an explanation to the unexpectedly fast water exchange rate observed on the squareantiprismatic isomers. I established a synthetic protocol that can be used for the attachment of the bifunctional ligand DO3A-pyNO-C to any amine-bearing molecule. I prepared a series of conjugates with polyamidoamine dendrimes and a conjugate with per-6-amino--cyclodextrine and...
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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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