Synthesis of dexrazoxane analogs

Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Marek Macuš Supervisor: Ing. Galina Karabanovich, Ph.D. Title of the thesis: Synthesis of dexrazoxane analogs Anthracycline antibiotics (ANT), such as daunorubicin, doxorubicin or epirubicin, belong amongst the most effective antineoplastic drugs. They are being used to treat leukemias as well as solid tumors. One of the limiting factors of these highly active substances is their cardiotoxicity. Supposedly, cardiotoxicity can originate in the following basis; either by the interaction with Fe ions which form reactive oxygen species (ROS) or directly caused by the inhibition of topoisomerase IIβ by ANTs in cardiomyocytes. Irreversible damage to heart muscle cells can lead to heart failure. Dexrazoxane (DEX) is the only drug clinically used for ANT-inducted cardiotoxicity prevention. DEX is a bisdioxopiperazine derivative, and its mechanism of action is not fully clear. There are two main hypotheses: 1. chelation of intracellular iron ions and reduction of ROS formation, 2. catalytic inhibition of topoisomerase IIβ. Figure 1: Structure of dexrazoxane and dexrazoxane analogues prepared in this thesis. The thesis aimed to prepare DEX analogues with a modified linker. Namely, the butane-2,3-..