Sep 13, 2019

Clarifying the Mechanism of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα and IIβ

Chemical Research in Toxicology
J Myles KeckJoseph E Deweese


Topoisomerase II is a nuclear enzyme involved in the maintenance of DNA and is an effective anticancer drug target. However, several clinical topoisomerase II-targeted agents display significant off-target toxicities and adverse events. Thus, it is important to continue characterizing compounds with activity against topoisomerase II. We previously analyzed α-(N)-heterocyclic thiosemicarbazone copper(II) complexes against human topoisomerase IIα (TOP2A), but humans also express topoisomerase IIβ (TOP2B), which has distinct functional roles. Therefore, we examined two α-(N)-heterocyclic thiosemicarbazone copper [Cu(II)] complexes for activity against TOP2B in a purified system. The Cu(II) complexes, Cu(APY-ETSC)Cl and Cu(BZP-ETSC)Cl, were examined using plasmid DNA cleavage, supercoiled DNA relaxation, enzyme inactivation, protein cross-linking, DNA ligation, and ATP hydrolysis assays with TOP2B to determine whether these compounds act similarly against both enzymes. Both of the Cu(II) thiosemicarbazone (Cu-TSC) complexes we tested disrupted the function of TOP2B in a way similar to the effect on TOP2A. In particular, TOP2B DNA cleavage activity is increased in the presence of these compounds, while the relaxation and ATPase acti...Continue Reading

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Mentioned in this Paper

ZEB1 protein, human
Antineoplastic Agents
copper-thiosemicarbazone complex
DNA Repair
Complex (molecular entity)
Transcription, Genetic
Virus Replication
DNA topoisomerase II alpha
DNA Supercoiling Activity

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