Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα : dynophore-derived discovery

Herlah, Barbara (author), Janežič, Matej (author), Ogris, Iza (author), Golič Grdadolnik, Simona (author), Kološa, Katja (author), Žabkar, Sonja (author), Žegura, Bojana (author), Perdih, Andrej (author)

The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.

• Language: English
• Keywords: topoisomerase II, catalytic inhibitors, chemotherapy, DNA damage, cancer
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 18 str.
• Numbering: Vol. 175, art. 116676
• PID: 20.500.12556/RUL-166737
• UDC: 615.9
• ISSN on article: 1950-6007
• DOI: 10.1016/j.biopha.2024.116676
• COBISS.SI-ID: 196316419
• Publication date in RUL: 23.01.2025

Record is a part of a journal

• Title: Biomedicine & pharmacotherapy
• Shortened title: Biomed. pharmacother.
• Publisher: Éditions scientifiques et médicales Elsevier
• ISSN: 1950-6007
• COBISS.SI-ID: 23136261

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: terapija z zdravili