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

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

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.

• Jezik: Angleški jezik
• Ključne besede: anticancer drugs, ATP-competitive inhibitors, catalytic inhibitor, cytotoxicity, human DNA topoisomerase II
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: 21 str.
• Številčenje: Vol. 249, art. 115116
• PID: 20.500.12556/RUL-144331
• UDK: 577.27:615.28
• ISSN pri članku: 0223-5234
• DOI: 10.1016/j.ejmech.2023.115116
• COBISS.SI-ID: 141491715
• Datum objave v RUL: 15.02.2023

Gradivo je del revije

• Naslov: European journal of medicinal chemistry
• Skrajšan naslov: Eur. j. med. chem.
• Založnik: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: ATP-kompetitivni katalitični zaviralec, človeška DNA topoizomeraza II, rak, medicina, farmacevtska kemija, citotoksičnost