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Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Jan Šůs Supervisors: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid Anthracyclines (ANTs) such as doxorubicin or daunorubicin are widely used anticancer drugs. However, their administration is associated with high risk of cardiotoxicity. Chronic ANT cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of ANTs with intracellular iron ions leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. However, recent studies showed that the mechanism of action is more complex and the inhibition of topoisomerase IIβ (TOP2β) may play a crucial role. The only drug preventing cardiotoxicity of ANTs with established clinical efficacy is dexrazoxane (DEX). The mechanism of action of DEX is not fully elucidated, it probably involves either chelation of intracellular ions by its metabolite ADR-925 (Fig. 1) or the inhibition of TOP2β by the parent compound. Fig. 1. Dexrazoxane and its...
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Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Jan Šůs Supervisors: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid Anthracyclines (ANTs) such as doxorubicin or daunorubicin are widely used anticancer drugs. However, their administration is associated with high risk of cardiotoxicity. Chronic ANT cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of ANTs with intracellular iron ions leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. However, recent studies showed that the mechanism of action is more complex and the inhibition of topoisomerase IIβ (TOP2β) may play a crucial role. The only drug preventing cardiotoxicity of ANTs with established clinical efficacy is dexrazoxane (DEX). The mechanism of action of DEX is not fully elucidated, it probably involves either chelation of intracellular ions by its metabolite ADR-925 (Fig. 1) or the inhibition of TOP2β by the parent compound. Fig. 1. Dexrazoxane and its...
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Synthesis of precursors of 4-quinolones against Trypanosoma brucei for 18F-radiolabelling
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Jan Šůs Supervisors: Prof. Dr. Ulrike Holzgrabe PharmDr. Jaroslav Roh, PhD Title of diploma thesis: Synthesis of precursors of 4-quinolones against Trypanosoma brucei for 18F-radiolabelling Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic disease caused by two subspecies of Trypanosoma brucei (T.b.gambiense and T.b.rhodesiense). This parasite is transmitted by the bite of infected tsetse flies. The sleeping sickness occurs in two clinical stages. The first one is characterized by the multiplication of parasites in the blood and lymphatic system. Very nonspecific symptoms, like fever, swollen lymph nodes, joint pain and headache are present. After a few weeks, a parasite crosses the blood-brain barrier and neurological symptoms like behavior changes, confusion, aggression and disruptions of sleep cycle appear. A coma and death results, if left untreated. Nowadays, there are only five drugs available for the medical treatment of HAT. Suramin and pentamidine are used for the first stage, melarsoprol and eflornithine in combination with nifurtimox for the second one. Life threatening side-effects and a developing of resistances are the reasons,...
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