Anticancer Active Cyclometalated Iridium(III) Complexes Bearing Substituted 1,2,4-Triazine: Biomolecular Interactions and Gene Expression Studies in Drosophila melanogaster

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Abstract Cationic bis-heteroleptic Ir(III) complexes (Ir1–Ir3) bearing 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (pdpt) as an ancillary ligand were synthesized using three different cyclometallating ligands. Structural characterization by FT-IR, ESI-MS and 1D/2D NMR confirmed the formation of the complexes, while the molecular structure of Ir1 was elucidated from single-crystal X-ray diffraction. Photophysical studies revealed that all complexes exhibited red-light emission under UV light. The complexes demonstrated high kinetic stability under biologically relevant conditions. Biomolecular studies in cell-free conditions showed strong binding affinities toward DNA and BSA, with Ir1 exhibiting the highest interaction. Cytotoxicity evaluation against MCF-7, MDA-MB-231, and A549 cancer cell lines revealed significant anticancer activity. Among the three complexes, Ir2 displayed the highest cytotoxicity, whereas Ir3 showed the least potency. The exploration of selectivity toward MCF10A disclosed the optimal balance between anticancer efficacy and selectivity of Ir1. The in vitro noncytotoxicity of these complexes against HEK-293 cells further highlighted the superior activity relative to the conventional Pt-based cancer drugs. The anticancer efficacy of complexes was examined in treated MCF-7 cancer cells through DAPI nuclear staining assays and arrest of the cell cycle at the G0/G1 phase, analyzed from flow cytometry. Finally, in vivo toxicity screening in Drosophila melanogaster connected gene expression changes to developmental abnormalities, confirming Ir2 as the most cytotoxic complex.

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