Structural and Metal Ion Effects on Human Topoisomerase IIα Inhibition by α-(N)-Heterocyclic Thiosemicarbazones

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Chemical Research in Toxicology


Our previous research has shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα), while the ligands without metals do not. To find out the structural elements of TSC that are important for inhibiting TopoIIα, we have synthesized two series of α-(N)-heterocyclic TSCs with various substrate ring segments, side chain substitutions, and metal ions, and we have examined their activities in TopoIIα-mediated plasmid DNA relaxation and cleavage assays. Our goal is to explore the structure-activity relationship of α-(N)-heterocyclic TSCs and their effect on TopoIIα. Our data suggest that, similar to Cu(II)-TSCs, Pd(II)-TSC complexes inhibit plasmid DNA relaxation mediated by TopoIIα. In TopoIIα-mediated plasmid DNA cleavage assays, the Cu(II)-TSC complexes induce higher levels of DNA cleavage than their Pd(II) counterparts. The Cu(II)-TSC complexes with methyl, ethyl, and tert-butyl substitutions are slightly more effective than those with benzyl and phenyl groups. The α-(N)-heterocyclic ring substrates of the TSCs, including benzoylpyridine, acetylpyridine, and acetylthiazole, do not exhibit a significant difference in TopoIIα-mediated DNA cleavage. Our data suggest that the metal ion of TSC complexes plays a predominant role in inhibition of TopoIIα, the side chain substitution of the terminal nitrogen plays a secondary role, while the substrate ring segment has the least effect. Our molecular modeling data support the biochemical data, which together provide a mechanism by which Cu(II)-TSC complexes stabilize TopoIIα-mediated cleavage complexes.

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