C-Geranylated flavanone diplacone enhances in vitro antiproliferative and anti-inflammatory effects in its copper(II) complexes

Two copper(II) complexes containing diplacone (H₄dipl), a naturally occurring C-geranylated flavanone derivative, in combination with bathophenanthroline (bphen) or 1,10-phenanthroline (phen) with the composition [Cu₃(bphen)₃(Hdipl)₂]⋅2H₂O (1) and {[Cu(phen)(H₂dipl)₂]⋅1.25H₂O}_n (2) were prepared and characterized. As compared to diplacone, the complexes enhanced in vitro cytotoxicity against A2780 and A2780R human ovarian cancer cells (IC₅₀ ≈ 0.4–1.2 μM), human lung carcinoma (A549, with IC₅₀ ≈ 2 μM) and osteosarcoma (HOS, with IC₅₀ ≈ 3 μM). Cellular effects of the complexes in A2780 cells were studied using flow cytometry, covering studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production. These results uncovered a possible mechanism of action characterized by the G2/M cell cycle arrest. The studies on human endothelial cells revealed that complexes 1 and 2, as well as their parental compound diplacone, do possess anti-inflammatory activity in terms of NF-κB inhibition. As for the effects on PPARα and/or PPARγ, complex 2 reduced the expression of leukocyte adhesion molecules VCAM-1 and E-selectin suggesting its dual anti-inflammatory capacity. A wide variety of Cu-containing coordination species and free diplacone ligand were proved by mass spectrometry studies in water-containing media, which might be responsible for multimodal effect of the complexes.