Synthesis of Gold(I) Complexes Containing Cinnamide: In Vitro Evaluation of Anticancer Activity in 2D and 3D Spheroidal Models of Melanoma and In Vivo Angiogenesis.

A series of alkynylgold(I) phosphine complexes containing methoxy-substituted cinnamide moieties (3a-3c and 4a-4c) have been synthesized and characterized. All of the synthesized complexes were evaluated for their cytotoxicity against three human cancer cell lines A549 (lung), D24 (melanoma), and HT1080 (fibrosarcoma) and the human embryonic kidney 293 cell line (Hek293T) as a proxy model for noncancer cells. Most of the synthesized compounds showed antiproliferative activity against cancer cell lines at low micromolar concentrations. Among these, complex 3c showed a broad spectrum of anticancer activity with IC50 values in the range of 1.53-6.05 μM against all tested cancer lines. Complex 3c possessed 20 times higher cytotoxicity than the reference drug cisplatin against D24 melanoma cells and showed significant anticancer activity in 3D spheroidal models of melanoma cells. Mechanistic investigations of 3c activity indicate thioredoxin reductase inhibition through steric and hydrogen-bonding interactions, followed by the induction of oxidative stress and a mitochondrial pathway of cell death. Compound 3c also showed significant antiangiogenic properties in a transgenic zebrafish Tg(fli1a:EGFP) in vivo model.