DNA topoisomerases comprise an important family of enzymes that catalyse the induction of topological changes (e.g. relaxation/
supercoiling, catenation/decatenation and knotting/unknotting) in the DNA molecule. These enzymes perform their functions by creating
transient either single-stranded or double-stranded breaks in the DNA molecule. Due to their ability to modulate the topology of the
DNA molecule, DNA topoisomerases play vital roles in replication, transcription, chromosome separation and segregation, and thus represent
an important collection of design targets for novel anticancer drugs. The aim of this review is to provide an overview of the development
of catalytic inhibitors of the human topoisomerase IIα enzyme - an important member of the DNA topoisomerase family - as potential
novel anticancer agents. The group of catalytic topoII inhibitors is classified into four types according to their molecular mechanism
of action: inhibitors that bind to the ATP binding site, inhibitors that prevent the ATP hydrolysis step and trap the enzyme in a
closed clamp, inhibitors that block the DNA cleavage and inhibitors that prevent the enzyme binding to the DNA. One of the important
considerations highlighted throughout this review is the structure-based perspective of inhibitor design, giving the reader a medicinal
chemist’s perspective on this vibrant and active field of drug design research.
Keywords: DNA topoisomerase II, catalytic inhibitors, ICRF-187 inhibitor, ATP binding site, anticancer agents, medicinal chemistry, drug design, supercoiling, knotting, DNA molecule.
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