Synthesis and anti-cancer investigations of copper(II) complexes based on adenine

•Two novel Cu(II) complexes based on adenine show potent anticancer activity.•Cytotoxicity surpasses cisplatin, especially with a methyl group at C-5.•Cu(II) complex C2 emerges as a powerful chemotherapeutic agent.•C2′s efficacy involves ROS elevation, DNA damage, mitochondrial disruption, and apoptosis.•Adenine-based Cu(II) complexes, particularly C2, demonstrate superior cytotoxicity, marking a significant advance in anticancer drug discovery. Platinum-based chemotherapeutics have played a critical role in oncology for decades. However, their broader utility is hindered by the advent of severe side effects and the emergence of drug resistance. The pursuit of alternative agents, particularly non-platinum (non-Pt) metal complexes, has gained momentum in current research. Designing efficacious non-Pt metal agents that target DNA poses a complex challenge. In this study, we present the strategic design, synthesis, and thorough characterization of two innovative copper(II) complexes leveraging adenine as a ligand, a potential avenue to overcome these challenges. Our investigation demonstrates the superior cytotoxicity of these copper(II) complexes compared to the benchmark cisplatin, with complex C2 exhibiting the most promising anticancer activity, showcasing an impressive IC50 value of 4.51 μM in MGC-803 cells. Mechanistic insights underscore that complex C2 executes its cytotoxic effects by instigating DNA damage, orchestrating cell cycle arrest at the G2 phase, perturbing mitochondrial membrane potential, inducing ROS production, and ultimately triggering apoptotic pathways. These findings significantly emphasize the potential of designing novel adenine-based anticancer metal complexes targeting DNA, portraying a compelling trajectory for advancing anticancer drug development. Mechanisms of C2 Compound-induced Cytotoxicity in Cancer Cells Synopsis: This study highlights the pursuit of non-platinum metal complexes as alternative anticancer agents to overcome drug resistance and severe side effects associated with platinum-based chemotherapeutics. Copper(II) complex C2 emerges as a promising candidate, demonstrating superior cytotoxicity by targeting DNA and triggering multiple pathways for apoptosis. [Display omitted]