In vitro study of novel catalytic inhibitors of topoisomerase II.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Tomáš Trnka Supervisor: Prof. PharmDr. Tomáš Šimůnek, PhD. Title of diploma thesis: In vitro study of new catalytic topoisomerase II inhibitors A wide range of drugs of different groups can be used for the pharmacotherapy of cancer. One of them are anthracycline antibiotics, which have been used in chemotherapy since the second half of the 20th century. Despite of their usage, there is still widespread concern about myocardial damage due to their cardiotoxic effect. The only cardioprotective agent, which is used is dexrazoxane (DEX). The mechanism of its effect has been traditionally supposed to consist on iron ion chelation, but recently, attention has shifted to its effects on topoisomerase II (TOP2), which could be the key element in the development of anthracycline cardiotoxicity. Apart from the positive effects on treatment, DEX has been also connected with its negative impact, due to the possible occurrence of acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome. The aim of our work was to assess the effects of other TOP2 catalytic inhibitors - novobiocin (NB), merbarone (MER), BNS-22, suramin (SUR) and also XK-469, for which was synthesized a series of analog substances..