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Synthesis and applications of fluorophosphonates
Cherkupally, Prabhakar ; Beier, Petr (advisor) ; Hermann, Petr (referee) ; Kvíčala, Jan (referee)
In the Introduction part of this thesis, the chemistry of organo-fluorine compounds including the electronic properties that fluorine impacts onto organic molecules, steric effects, lipophilicity and other characteristics as well as applications and important features of organo-fluorine compounds are briefly discussed. Moreover, summary of the methods for their preparation, modern methods for fluorinations and enantioselective fluorinations, and fluoroalkylation methodologies in organic synthesis are described. Additionally, the chemistry of fluorinated phosphonates including their preparations, important applications and the chemistry of α,α-difluorophosphonates are discussed. The Results and discussion part describes nucleophilic trifluoromethylation of various electrophilic substrates using diethyl trifluoromethylphosphonate. Furthermore, efficient stereoselective synthesis of fluorovinylphosphonates by a base-induced HF elimination of α,α-difluorophosphonates is explained. In addition, synthesis of number of new, structurally diverse compounds, having a difluorophosphonate moiety using the reaction of diethyl difluoromethylphosphonate with various α,β-unsaturated carbonyl compounds, Michael acceptors and imines are reported. Also, preliminary experiments dealing with nucleophilic reactions of...
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Macrocyclic chelators for metal-radionuclides
Málková, Michaela ; Hermann, Petr (advisor) ; Příhoda, Jiří (referee) ; Komárek, Pavel (referee)
5 Abstract in English Complexation properties of structurally related macrocyclic polyazachelators with different metal ions suitable for a medicinal use were studied. In the present work, a study of chelators formally derived from H4dota (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) by replacement of one or four carboxylic groups with a phosphorus acid moiety(ies) was performed. Three new chelators were studied: H4do3apABn (10-{[(4-aminobenzyl)hydroxyphosphoryl]methyl}- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), H5do3apPrA (10-{[(2-carboxyethyl)hydroxyphosphoryl]methyl}- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), H4dotpOEt [1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrakis(methylphosphonic acid monoethylester)] In addition new data on stability constants of transition metal complexes of H5do3ap, 10-[(dihydroxyphosphoryl)methyl]- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, are presented. The achieved results suggest that all studied chelators form complexes with di- and trivalent metal ions with sufficient thermodynamic stability and kinetic inertness for the potential medicinal applications. The formation rate of complexes of the monophosphonic/inic chelators is comparable to that of the H4dota complexes. The formation rate of the complexes depends highly on...
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NMR study of solution dynamics of LnIII complexes of monophosphorus H4dota analogues
Svítok, Adam ; Hermann, Petr (advisor) ; Dračínský, Martin (referee)
Lanthanides have several specific properties which cannot be found for other elements in the periodic table. Among various applications of lanthanides, complexes of LnIII ions are used in medicine, e.g., as contrast agents in MRI, as luminescent probes or as radiopharmaceuticals, where their specific properties are important. These complexes must be kinetically inert to prevent release of highly toxic "free" LnIII ions. This requirement is fulfilled with pre-organized ligands such as analogues of H4dota (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid). Many of important properties of LnIII complexes of H4dota, such as relaxivity, isomerism and fluxionality, depend on the solution dynamics of the complexes. However, the knowledge of this solution dynamics is limited for LnIII complexes of H4dota derivatives with phosphonate or phosphinate pendant arms. Recently, a new dynamical process where phosphonate oxygen atoms interchange through a bidentate phosphonate intermediate ("a phosphonate rotation") has been proposed by DFT calculations but unconfirmed experimentally. To prove the process experimentally, solution dynamics of LnIII complexes of monophosphonate and monophosphinate derivatives of H4dota was investigated. Especially, to examine the "P-rotation", 17 O NMR spectroscopy was used...
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Synthesis of unsymmetric DOTA derivatives and study of their complexes
Obuch, Jakub ; Hermann, Petr (advisor) ; Drahoš, Bohuslav (referee)
Lanthanide(III) complexes are compounds with both diagnostic and therapeutic applications. For diagnostic applications, they are used as contrast agents for imaging techniques such as MRI, PET or SPECT. In therapy, complexes of beta or alpha particle- emitting radionuclides are used. If the complexes contain protonable groups, their behaviour is dependent on pH of the solution. Protonation of these groups should occur close to the physiological pH. If the efficiency (relaxivity) of the MRI contrast agent is dependent on protonation state, this method can be used for determination of pH of tissues in vivo. For radiopharmaceuticals, fast complexation of short-lived metal radionuclides is important and protonation might significantly accelerate the complex formation. For therapeutic applications, possibility of labelling at low temperatures when heat-sensitive biovectors (e.g. antibodies) do not decompose. To assess the effect of protonation of amino group in the vicinity of the metal ion, amino-bis(phosphinate) pendant arm was proposed, where the dissociation constant of the amino group below the physiological pH can be expected. Three ligands containing this group and DO3A fragment were prepared and their complexes were studied to assess aforementioned possible uses in medicine. Their structure and...
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Fluorinated macrocycles for 19F MRI
Šmelko, Andrej ; Hermann, Petr (advisor) ; Blahut, Jan (referee)
19 F MRI contrast agents are relatively new, developing field of medical and chemical sciences. In this Theses, based on previous results in this area, new type of Ni2+ complex with possible 19 F MRI applications was synthesized and characterized by relaxometric measurements.
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Large macrocycles and their complexes
Faltejsek, Jan ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Macrocyclic ligands have been used in radiomedicine for a long time. These ligands have been studied mainly in terms of complexation of heavy metal ions and possible use of these com- plexes in diagnostics and radiotherapy. Recent studies have highlighted the potential use of actinium-225 as an alpha-emitting radionuclide. This isotope is suitable for a precise treatment of micrometastases as it emits a cascade of high-energy but short-range alpha radiation. Due to the high linear energy transfer of the emitted particles, the tumor cells at a given location in the patient's body are completely destroyed. This work deals with the preparation and char- acterization of 18-membered polyazamacrocyclic ligands that can be used for complexation of this radioisotope. The prepared substances were characterized by potentiometry, NMR, MS and EA. Thermodynamic data of the complexes of these ligands with "model" heavy metal ions (Ca2+ , Sr2+ and Ba2+ ) were obtained using potentiometry. For cerium(III) complexes with prepared ligands, the pH-dependent kinetics of their formation were studied, and the results of these measurements indicate the possibility of using these ligands in radiomedicine. Keywords: macrocyclic ligands, heavy metal complexes, radiotherapy 1
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Synthesis of asymetrically substituted derivatives of cyclam
Chrappa, Michal ; Hermann, Petr (advisor) ; Kubíček, Vojtěch (referee)
Copper radionuclides have a potential in nuclear medicine as diagnostic or therapeutic agents. Copper isotopes are used in the form of coordination compounds with various ligands, such as derivatives of 1,4,8,11-tetraazacyclotetradecane (cyclam). Properties of such complexes can be modified by pendant arms introduced on amino groups of cyclam. This thesis is aimed on the synthesis of asymmetrically substituted cyclam derivative with derivatives of phosphorous acids in 1,8- position. In spite of the fact, that the target ligand has not been successfully synthesised, various possibilities of substitution on diprotected cyclam were investigated. New possibilities of orthogonal protection of cyclam were found as well. Keywords: PET, SPECT, copper complexes, cyclam protection, phosphonic acids
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