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

Area of Science:

• Inorganic Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Triple-negative breast cancer (TNBC) remains a challenging subtype with limited targeted therapies.
• Gold(I) complexes are emerging as promising anticancer agents due to their unique mechanisms of action.
• Tricoordinate gold(I) complexes offer tunable structures for enhanced therapeutic efficacy.

Purpose of the Study:

• To synthesize and characterize novel tricoordinate gold(I) complexes incorporating biaryldialkyl phosphine ligands.
• To evaluate the in vitro cytotoxicity of these complexes against human TNBC cell lines.
• To investigate the in vivo anticancer potential and preliminary tolerability of a lead complex.

Main Methods:

• Synthesis and full characterization of 14 novel (Au(R)[N̂N])+ complexes.
• In vitro cytotoxicity assays using MDA-MB-231 and MDA-MB-468 TNBC cell lines.
• In vivo studies in a metastatic TNBC mouse model, including tumor growth inhibition assessment.

Main Results:

• Complexes exhibited submicromolar cytotoxic activity (IC50: 0.4-5.0 μM) against TNBC cells.
• Complex 2e demonstrated high potency in vitro, reducing 3D mammosphere viability and inducing apoptosis via endoplasmic reticulum stress.
• Significant tumor growth inhibition was observed in vivo with complex 2e, alongside good tolerability.

Conclusions:

• Phosphine-supported tricoordinate gold(I) complexes represent a promising new class of anticancer agents.
• Complex 2e shows significant therapeutic potential for metastatic TNBC, with demonstrated in vitro and in vivo efficacy.
• This study establishes the in vivo anticancer capability of this gold(I) complex class, expanding their therapeutic scope.