Ligand Electronics Dictate Geometry, Stability, and Cancer Cell Toxicity in Carbon-Stabilized Gold(III) Macrocycles

Strategies for rationally designing gold-based chemotherapeutics remain limited by an incomplete understanding of how ligand electronics shape structure and biological function. Here, we establish a direct link between σ-donor strength, geometric distortion, and anticancer activity across a series of carbon-stabilized Au(III) bisphosphine macrocycles derived from N,N'-(1,2-phenylene)bis(2-(diphenylphosphino)benzamide) (dppbH₂) and electronically tuned cyclometalated [C^N] templates. Systematic installation of substituents that modulate σ-donation to Au(III) produces predictable shifts in Au-C and Au-P bond lengths, trans bite angles, and square planar deformation. σ-donor character of complexes influences geometric distortion, aqueous stability, and up to an order-of-magnitude higher cytotoxicity in triple-negative breast cancer and estrogen receptor-positive models compared to cisplatin. Mechanism of action studies supports acute mitochondrial uncoupling and mtROS production, leading to cell death by this class of compounds. This electronic-structural-biological correlation provides a rare, experimentally validated design principle for Au(III) scaffolds and positions electronically tuned macrocycles as a chemically tractable platform for targeting intracellular pathways.