Syntéza kardioprotektivních chelátorů odvozených od diethylentriaminopentaoctové kyseliny

Šůs, Jan

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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