Engineering amino acid-derived Au(III) macrocycles as bioactive chemical biology agents

Macrocyclic scaffolds have become increasingly important in modern drug discovery owing to their structural preorganization, favorable pharmacological properties, and widespread incorporation into peptide- and amino acid-based therapeutics. In contrast, the integration of biologically relevant amino acid architectures into organometallic macrocycles remains largely unexplored, particularly for redox-active gold complexes. Herein, we report the design, synthesis, structural characterization, and biological evaluation of a new class of l-lysine-derived Au(III) bisphosphine macrocycles, exemplified by JH-121, together with related amino acid-expanded analogues. Incorporation of the flexible lysine backbone provides a distinct ligand environment that preserves the stability of the Au(III) center while imparting unique redox properties absent in conventional nitrogen-donor macrocycles. JH-121 exhibits potent antiproliferative activity across multiple breast cancer cell lines and inhibits breast cancer mammosphere growth under the experimental conditions examined. Spectroscopic, stability, and electrochemical studies demonstrate that the expanded amino acid backboned macrocycle has a distinct, irreversible, thiol-triggered Au(III)-Au(I) conversion, leading to the formation of an isolable Au(I) species that retains robust anticancer activity. These findings identify amino acid-derived bisphosphine macrocycles as a versatile platform for engineering the redox behavior of gold complexes and establish biologically inspired ligand design as a promising strategy for the development of next-generation gold-based anticancer therapeutics.