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.