20.500.12556/DiRROS-19029 Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα dynophore-derived discovery Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα: dynophore-derived discovery 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. topoisomerase II catalytic inhibitors chemotherapy DNA damage cancer true false true Biomedicine & pharmacotherapy Angleški jezik Ni določen © 2024 The Authors. Neznano 2024-06-03 09:43:26 2024-06-03 09:55:15 2024-06-04 03:38:29 0000-00-00 00:00:00 2024 0 0 Soavtorji: Matej Janežič, Iza Ogris, Simona Golič Grdadolnik, Katja Kološa, Sonja Žabkar, Bojana Žegura, Andrej Perdih; Nasl. z nasl. zaslona; Opis vira z dne 22. 5. 2024; str. 1-18 [article no.] 116676 Vol. 175 Jun. 2024 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 2024-06-01 615.9 1950-6007 10.1016/j.biopha.2024.116676 196316419 https://doi.org/10.1016/j.biopha.2024.116676 1 f8350d78-217c-11ef-9c9e-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=26114 RAZ_Herlah_Barbara_2024.pdf RAZ_Herlah_Barbara_2024.pdf 1 BD6F61C36048CEF603C2D04E9673B6BD d2c5d2384c87799e1e2b37ff890b6e09378be5ac7ae1482e7aaadf5b1790bfd6 7924fc16-217e-11ef-9c9e-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=26115 Kemijski inštitut 0 0 0