Expanding Three-Coordinate Gold(I) Anticancer Agent Chemical Space

We report the synthesis and characterization of 14 complexes of the type (Au(R)[N̂N])+, where R = tunable biaryldialkyl phosphine ligands and [N̂N] = bidentate phenanthroline derivatives as anticancer agents. These novel tricoordinate Au(I) complexes were characterized and evaluated in metabolically differentiated triple negative breast cancer (TNBC) cell lines for their cytotoxicity potential. The complexes demonstrated submicromolar cytotoxic activity against human breast cancer cells MDA-MB-231 or MDA-MB-468 with IC50’s in the range of 0.4–5.0 μM. Complex 2e shows high potency in vitro and decreases 3D-breast cancer mammosphere viability. Mechanistic studies show 2e promotes cell death by apoptosis with plausible mode of action via endoplasmic reticulum stress induction. Tumor growth inhibition in a metastatic TNBC mouse model was observed, demonstrating 2e′s translational capability. We show for the first time the in vivo anticancer potential of a phosphine-supported tricoordinate-Au(I) complex in mice with suitable tolerability. These studies further expand the therapeutic potential of tricoordinate-Au(I) complexes.