Mitochondrial apoptosis and DNA intercalation synergistically driven by organotin acridine-9-carboxylate complexes...

Four organotin acridine-9-carboxylate complexes (C1-C4) were successfully synthesized by the reaction of 9-acridinecarboxylic acid (YCOOH) with organotin precursors. The structures of these complexes were systematically characterized using elemental analysis, IR, NMR, X-ray single-crystal diffraction, X-ray powder diffraction and thermogravimetric analysis. Among them, the tributyltin complex C4 exhibited the most potent in vitro antiproliferative activity against HepG2, MCF-7, and NCI-H460 cancer cell lines, with IC₅₀ values as low as 0.08 μM against HepG2 cells. Mechanistic studies identified two functional pathways: (i) DNA intercalation, as evidenced by UV-Vis, fluorescence titrations, viscosity measurements, and molecular docking, which directly disrupts DNA architecture; and (ii) mitochondria-mediated apoptosis, characterized by collapse of mitochondrial membrane potential (ΔΨ_m), cytochrome c (CytC) release, elevated ROS generation, upregulation of Bax and Cleaved-caspase-3, and downregulation of Bcl-2. Importantly, these two pathways act synergistically: DNA intercalation triggers early nuclear stress, which amplifies mitochondrial dysfunction and ROS burst, thereby lowering the apoptotic threshold and enhancing the overall cytotoxic efficacy. Collectively, the dual DNA-mitochondria targeting and their cooperative action establish acridine-based organotin complexes as promising anticancer candidates.