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

Skok, Žiga (author), Durcik, Martina (author), Zajec, Živa (author), Gramec, Darja (author), Bozovičar, Krištof (author), Pišlar, Anja (author), Tomašič, Tihomir (author), Zega, Anamarija (author), Peterlin-Mašič, Lucija (author), Kikelj, Danijel (author), Zidar, Nace (author), Ilaš, Janez (author)

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 IC$_{50}$ value of 0.67 μM against DNA topoisomerase IIα. Compound 53b showed exceptional activity on cancer cell lines with IC$_{50}$ 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.

• Language: English
• Keywords: anticancer drugs, ATP-competitive inhibitors, catalytic inhibitor, cytotoxicity, human DNA topoisomerase II
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 21 str.
• Numbering: Vol. 249, art. 115116
• PID: 20.500.12556/RUL-144331
• UDC: 577.27:615.28
• ISSN on article: 0223-5234
• DOI: 10.1016/j.ejmech.2023.115116
• COBISS.SI-ID: 141491715
• Publication date in RUL: 15.02.2023

SKOK, Žiga, DURCIK, Martina, ZAJEC, Živa, GRAMEC, Darja, BOZOVIČAR, Krištof, PIŠLAR, Anja, TOMAŠIČ, Tihomir, ZEGA, Anamarija, PETERLIN-MAŠIČ, Lucija, KIKELJ, Danijel, ZIDAR, Nace and ILAŠ, Janez, 2023, ATP-competitive inhibitors of human DNA topoisomerase IIα with improved antiproliferative activity based on N-phenylpyrrolamide scaffold. European journal of medicinal chemistry [online]. 2023. Vol. 249,  115116. [Accessed 22 April 2025]. DOI 10.1016/j.ejmech.2023.115116. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=144331

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: ATP-kompetitivni katalitični zaviralec, človeška DNA topoizomeraza II, rak, medicina, farmacevtska kemija, citotoksičnost