(Dipyrido[3,2-a:2',3'-c]phenazine)(glycinato)copper(II) perchlorate: a novel DNA-intercalator with anti-proliferative activity against thyroid cancer cell lines

Abstract

A novel copper(II) heteroleptic complex of dipyrido[3,2-a:2',3'-c]phenazine (dppz) and glycinato (gly) as chelating ancillary ligand, [Cu(dppz)(gly)]ClO(4) (1), was synthesized and characterized. X-ray crystallography revealed that the coordination geometry of the cationic [Cu(dppz)(gly)](+) unit is hexacoordinated and shows a distorted octahedral coordination geometry in the solid state, with the N,N and N,O chelating atoms of dppz and glycinato, respectively, in the square plane and in which the planar units are connected in a monodimensional polymeric array by the apical copper coordination of the second carboxylic oxygen atom. Biological assays showed that 1 exhibits a remarkable anti-proliferative activity against the two human anaplastic thyroid cancer cell lines 8505c (BrafV600E/V600E) and SW1736 (BrafWT/V600E), in a dose- and time-dependent manner. In details, the IC(50) after 48 h of drug exposure was 2.86 ± 0.54 μM for SW1736 and 1.05 ± 0.48 μM for 8505c. On the other hand, the IC(50) shown by cis-diamminedichloroplatinum(II) (cisplatin) against the same cell lines was 2.50 ± 0.40 μM and 6.03 ± 0.78 μM, respectively. Optical microscopy observations, after 48 h of treatment, showed morphological cell changes typical of apoptosis, confirmed by DNA ladder assays. DNA interaction studies, performed by UV absorption spectrophotometry, circular dichroism and viscosimetry, clearly showed that [Cu(dppz)(gly)]ClO(4) is a DNA-intercalator, with a DNA-binding constant, K(b), of 2.1 × 10(6) M(-1), suggesting that the mechanism of the cytotoxic activity can be related to its DNA-binding.