DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule.
Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as
replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular
targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel
anticancer drugs especially supported by recent structural advances in the field.
The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase
IIα inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of
these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising
compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical
classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase IIα. In particular, this review focuses
on the currently available structure-based standpoint of molecular design and on the medicinal chemist’s perspective of this field of
anticancer drug design.
Keywords: DNA topoisomerase IIα, DNA poisons, intercalators, non-intercalators, redox-dependent poisons, inhibitors, anticancer agents, medicinal chemistry, drug design, cardiotoxicity
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