Ferrocene-promoted photoactivated DNA cleavage and anticancer activity of terpyridyl copper(II) phenanthroline complexes

Abstract

Ferrocene-appended copper(II) complexes [Cu(Fc-tpy)(B)](ClO₄)₂ (1-3) and [Cu(Ph-tpy)(dppz)](ClO₄)₂ (4) as control, where Fc-tpy is 4'-ferrocenyl-2,2':6',2"-terpyridine, Ph-tpy is 4'-phenyl-2,2':6',2"-terpyridine, and B is a phenanthroline base, viz., 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), were prepared and structurally characterized, and their DNA binding, photoactivated DNA cleavage activity, and cytotoxic properties were studied [Fc = (η⁵-C₅H₄)Fe^II(η⁵-C₅H₅)]. Complexes 1 and 3 as hexafluorophosphate salts were structurally characterized by X-ray crystallography. Molecular structures of [Cu(Fc-tpy)(phen)](PF₆)₂ (1a) and [Cu(Fc-tpy)(dppz)](PF₆)₂·MeCN (3a·MeCN) show a distorted square-pyramidal geometry at copper(II), with the Fc-tpy ligand and the phenanthroline base showing respective tridentate and bidentate binding modes. The phenanthroline base exhibits axial-equatorial bonding, while the Fc-tpy ligand binds at the basal plane. The complexes showed quasi-reversible cyclic voltammetric responses near 0.45 and -0.3 V vs SCE in aqueous DMF-0.1 M KCl assignable to the Fc⁺-Fc and Cu(II)-Cu(I) redox couples, respectively. The complexes bind to DNA, giving K_b values of 1.4 × 10⁴ to 5.6 × 10⁵ M^-1 in the order 4 ~3 > 2 > 1. Thermal denaturation and viscometric titration data suggest groove and/or partial intercalative mode of DNA binding of the complexes. The complexes showed chemical nuclease activity in the presence of 3-mercaptopropionic acid (0.5 mM) or H₂O₂ (0.25 mM). Complexes 2-4 showed plasmid DNA cleavage activity in visible light, forming •OH radicals. The Fc-tpy complex 3 showed better DNA photocleavage activity than its Ph-tpy analogue. The ferrocene moiety in the dppz complex 3 makes it more photocytotoxic than the Ph-tpy analogue 4 in HeLa cells.