Bioorganic Chemistry (2020)
Update date:2022-08-02
Topics:
Baran?oková, Michaela
Durcik, Martina
Gramec Skledar, Darja
Ila?, Janez
Kikelj, Danijel
Peterlin Ma?i?, Lucija
Skok, ?iga
Toma?i?, Tihomir
Zega, Anamarija
Zidar, Nace
Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 μM) and ATPase assay (IC50 = 0.43 μM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 μM, respectively.
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