Publication in Journal of Inorganic Biochemistry

Heteroleptic copper(II) complexes of prenylated flavonoid osajin behave as selective and effective antiproliferative and anti-inflammatory agents


Authors: Ján Vančo, Zdeněk Trávníček Jan Hošek and Zdeněk Dvořák



Five heteroleptic copper(II) complexes (15), containing the combination of naturally occurred flavonoid osajin (HL) and various bidentate N-donor diimine ligands (N–N) with the general composition of [Cu(L)(N–N)]NO3 were prepared. The solution studies (conductivity measurements, ESI+MS) confirmed the 1:1 electrolyte nature of the complexes, their stability in water-containing media and uncovered redox mechanism of their biological activation by the interaction with Cys and GSH. The X-ray structural analysis proved the monodentate coordination the NO3 group to the copper(II) atom in the apical position of the spherical square-pyramidal coordination polyhedron. All the complexes were screened for in vitro cytotoxicity against human cancer cell lines (MCF-7, HOS, A549, PC-3, A2780, A2780R, Caco-2 and THP-1) revealing significant antiproliferative effect (IC50 » 1 – 23 mM), in all cases better than the reference standard drug cisplatin. Overall, the most promising results were achieved for complexes 4 and 5 with IC50 » 1–3 mM. The complexes also showed negligible toxicity against human hepatocytes pointing out selectivity over cancer cells. Within the Casiopeínas family, the trend that the best cytotoxic effect in vitro was observed for Cu(II) acetylacetonato/glycinato complexes involving disubstituted and tetrasubstituted N-donor ligands based on 2,2’-bipyridine and 1,10-phenathroline moieties [4]. This fact may be connected with the increasing of the hydrophobicity, which was identified as one of the major molecular descriptors by the QSAR analysis in the group of Casiopeínas. The most active complexes 4 and 5 demonstrated ability to inhibit the inflammatory processes through inhibition of NFκB/AP-1 activity and inhibition of TNF-α production. On the other hand, all the complexes showed their ability to induce the oxidative stress at THP-1-XBlueTM-MD2-CD14 cells in the 200 nM concentration. It has been found that the coordination compounds under the study represent complexes with promising biological potential and that is why they deserve to be studied deeper with an accent to tune their composition, and as a consequence of this, to tune their antiproliferative and anti-inflammatory features.