2. Academic Validation
  3. ATP-competitive inhibitors of human DNA topoisomerase IIα with improved antiproliferative activity based on N-phenylpyrrolamide scaffold

ATP-competitive inhibitors of human DNA topoisomerase IIα with improved antiproliferative activity based on N-phenylpyrrolamide scaffold

  • Eur J Med Chem. 2023 Jan 18;249:115116. doi: 10.1016/j.ejmech.2023.115116.
Žiga Skok 1,  Martina Durcik 1,  Živa Zajec 1,  Darja Gramec Skledar 1,  Krištof Bozovičar 1,  Anja Pišlar 1,  Tihomir Tomašič 1,  Anamarija Zega 1,  Lucija Peterlin Mašič 1,  Danijel Kikelj 1,  Nace Zidar 1,  Janez Ilaš 2
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 2 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: [email protected].
PMID: 36689894 DOI: 10.1016/j.ejmech.2023.115116
Abstract

ATP-competitive inhibitors of human DNA Topoisomerase II show potential for becoming the successors of Topoisomerase II poisons, the clinically successful Anticancer drugs. Based on our recent screening hits, we designed, synthesized and biologically evaluated new, improved series of N-phenylpyrrolamide DNA Topoisomerase II inhibitors. Six structural classes were prepared to systematically explore the chemical space of N-phenylpyrrolamide based inhibitors. The most potent inhibitor, 47d, had an IC50 value of 0.67 μM against DNA Topoisomerase IIα. Compound 53b showed exceptional activity on Cancer cell lines with IC50 values of 130 nM against HepG2 and 140 nM against MCF-7 Cancer cell lines. The reported compounds have no structurally similarity to published structures, they are metabolically stable, have reasonable solubility and thus can serve as promising leads in the development of Anticancer ATP-competitive inhibitors of human DNA Topoisomerase IIα.

Keywords

ATP-competitive; Anticancer; Catalytic inhibitor; Cytotoxic; Human DNA topoisomerase II.

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