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

Area of Science:

• Inorganic Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Designing effective gold-based chemotherapeutics is hindered by limited understanding of how ligand electronics influence structure and biological activity.
• Gold(III) complexes offer potential anticancer properties but require rational design strategies.

Purpose of the Study:

• To establish a direct correlation between σ-donor strength, geometric distortion, and anticancer efficacy in gold(III) bisphosphine macrocycles.
• To develop a validated design principle for gold(III) scaffolds based on electronic-structural-biological relationships.

Main Methods:

• Synthesis of carbon-stabilized gold(III) bisphosphine macrocycles using electronically tuned cyclometalated [C^N] templates.
• Systematic modification of substituents to modulate σ-donation to gold(III).
• Analysis of structural parameters (bond lengths, bite angles, planar deformation) and biological activity (cytotoxicity, mechanism of action).

Main Results:

• Modulating σ-donor strength predictably altered gold-III complex geometry, including bond lengths and square planar deformation.
• Increased σ-donor character correlated with enhanced geometric distortion, improved aqueous stability, and significantly higher cytotoxicity against triple-negative breast cancer and estrogen receptor-positive models compared to cisplatin.
• Mechanism of action involves acute mitochondrial uncoupling and mitochondrial reactive oxygen species (mtROS) production, leading to cancer cell death.

Conclusions:

• The study provides an experimentally validated electronic-structural-biological correlation for designing gold(III) chemotherapeutics.
• Electronically tuned gold(III) macrocycles represent a promising and chemically tractable platform for developing novel anticancer agents targeting intracellular pathways.