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New synthesized ferrocenyl trizole nucleobase derivatives induced cell death by mitochondria mediated apoptosis in tumor cells in vitro

Taking into consideration the biological importance of ferroceneand nucleoside analogues, the synthesis of twenty mono- and bis-ferrocene conjugated nucleobases that are bridged by triazole linker was undertaken with the aim to evaluate their antioxidan tpotential and activity against various tumor cell lines. Radical scavenging capacity, measured by 1, 1-diphenyl-2- picrylhydrazyl(DPPH) and expressed as a % of DPPH reduction after 30 and60 min, was between 62 and 90 %. Antiproliferative capacities of ferrocene derivatives were tested by MTT test on adenocarcinoma, leukemia, lymphoma, and normal fibroblast like cells.According calculated IC50 values, selectivity index, and no cytostatic effect on normal Madin-Darby canine kidney fibroblast like cells (MDCK1), four derivatives were selected for further testing on effects on intracellular ROS accumulation, mitochondrial membrane potential dysfunction, as well as apoptosis and autophagy induction in treated tumor cells. Slight changes in ROS intracellular accumulation and activated autophagy were observed. Tested new synthesised derivatives induced disruptionin mitochondrial membrane potential (∆Ψm) and mitochondrial dysfunction, resulting in mitochondria swelling accompanied by activation of apoptosis in treated cells. Early apoptosis induction was determined in colon adenocarcinoma (CaCo-2), Burkitt lymphoma (Raji) and acute lymphoblastic leukemia (CCRF-CEM) cells after treatment with selected derivatives. In conclusion, obtained results contribute to better understanding of antiproliferative activity of new ferrocenyl triazole nucleobase derivatives.

bis-ferrocene conjugated nucleobases, antiproliferative activity, apoptosis, mitochondrial potential disruption, ROS accumulation

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