N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity

0583469 - BFÚ 2024 RIV IE eng J - Journal Article
Bresciani, G. - Červinka, Jakub - Kostrhunová, Hana - Biancalana, L. - Bortoluzzi, M. - Pampaloni, G. - Novohradský, Vojtěch - Brabec, Viktor - Marchetti, F. - Kašpárková, Jana
N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity.
Chemico-Biological Interactions. Roč. 385, NOV 1 2023 (2023), č. článku 110742. ISSN 0009-2797. E-ISSN 1872-7786
R&D Projects: GA ČR(CZ) GA23-06316S
Institutional support: RVO:68081707
Keywords : basis-sets * mechanisms * cisplatin * molecules * drugs * oxaliplatin * insertion * energies
OECD category: Biochemistry and molecular biology
Impact factor: 5.1, year: 2022
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S000927972300409X?via%3Dihub

The indole scaffold has been established as a key organic moiety for developing new drugs, on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2-5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2-6 are substantially stable in DMSO-d6 and DMEM-d solutions at 37 degrees C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogPow values in the range0.32 to 0.47), associated with appreciable water solubility. The complexes display selective antiproliferative potency towards several cancer cells in monolayer cultures, mainly in the low micromolar range, with reduced toxicity towards noncancerous epithelial cells. Thus, the cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceutical cisplatin. Comparing the antiproliferative activity obtained for complexes containing different ligands, we confirmed the importance of the indolyl group in the mechanism of antiproliferative activity of these complexes. Cell-based mechanistic studies suggest that the investigated diiron vinyliminium complexes (DVCs) show cytostatic rather than cytotoxic effects and subsequently induce a population of cells to undergo apoptosis. Furthermore, the molecular mechanism of action involves interactions with mitochondrial DNA and proteins, the reactive oxygen species (ROS)-scavenging properties and antioxidant activity of these complexes in cancer cells. This study highlights the importance of DVCs to their cancer cell activity and reinforces their prospective therapeutic potential as anticancer agents.
Permanent Link: https://hdl.handle.net/11104/0351439