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Synthesis of chelators for use in diagnostic imaging
Kretschmer, Jan ; Polášek, Miloslav (advisor) ; Kubíček, Vojtěch (referee) ; Hrubý, Martin (referee)
Metals play a crucial role in medicine as a part of therapeutic or diagnostic preparations. However, in the majority of cases, their properties cannot be utilized entirely in free ionic form. Organic molecules capable of chelation are used to open the full potential of the metal. The molecules are called chelators and are the core theme of this thesis. The most important function of these molecules is the chelation and coordination of the metal, but chelators can provide other important functionalities. This work, therefore, focuses on the design, synthesis, and application of such polyfunctional chelators and is divided into two parts: DO3A-Hyp This part of the thesis deals with chelators that can be used as amino acids to incorporate lanthanides into peptides. The developed chelators provide a short and rigid connection of the metal to the peptide chain. Tripeptides containing two units of such chelators with a central amino acid bearing a CF3 group were synthesized to demonstrate the capability of DO3A-Hyp building blocks. Two paramagnetic metals were combined within this tripeptide, and it was shown that such a rigid and locked system could be used for combining their magnetic susceptibility tensors. These magnetic susceptibility tensors were used for manipulation of the 19 F NMR shift of the CF3...
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Iron homeostasis in malaria
Wernerová, Klára ; Šuťák, Róbert (advisor) ; Voleman, Luboš (referee)
Although malaria is a well-studied infectious disease, we are still unable to fight it effectively, as evidenced by a large number of infected people. Many drugs are available against malaria. However, because of incessantly emerging resistances, new, more effective antimalarials need to be developed. One possibility is to target the parasite's iron metabolism, the essential element of all organisms. Iron participates in DNA synthesis, respiration, energy production. It acts as a cofactor of ribonucleotide reductase, and metalloproteins with FeS clusters or heme. During the infection, the parasite must compete with the host for nutrients, including iron. The mechanism of iron uptake or excretion in malaria parasite is not completely clear. Only two iron transporters are known, but it is already evident, that there must be more of them. The Plasmodium parasite digests a large amount of hemoglobin, which is degraded into free heme and denatured globin. Free heme is toxic to the cell though. Plasmodium defends itself from the toxicity of free heme by forming chemically inert hemozoin. This unique mechanism of protection against the free heme toxicity is very useful for Plasmodium and other blood parasites, but it also becomes an advantageous target for drugs because the mechanism is present only in...
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