Ferrocene-conjugated l-tryptophan copper(II) complexes of phenanthroline bases showing DNA photocleavage activity and cytotoxicity

Abstract

Ferrocene-conjugated l-tryptophan (l-Trp) reduced Schiff base (Fc-TrpH) copper(II) complexes [Cu(Fc-Trp)(L)](ClO4) of phenanthroline bases (L), viz. 2,2'-bipyridine (bpy in 1), 1,10-phenanthroline (phen in 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 4), were prepared and characterized and their photocytotoxicity studied. Cationic reduced Schiff base (Ph-TrpH) complexes [Cu(Ph-Trp)(L)(H₂O)](ClO₄) (L = phen in 5; dppz in 6) having the ferrocenyl moiety replaced by a phenyl group and the Zn(II) analogue (7) of complex 4 were prepared and used as control species. The crystal structures of 1 and 5 with respective square-planar CuN₃O and square-pyramidal CuN₃O₂ coordination geometry show significantly different core structures. Complexes 1-4 exhibit a Cu(II)-Cu(I) redox couple near -0.1 V and the Fc⁺-Fc couple at ~0.5 V vs SCE in DMF-0.1 M [Buⁿ₄N](ClO₄) (Fc = ferrocenyl moiety). The complexes display a copper(II)-based d-d band near 600 nm and a Fc-centered band at 450 nm in DMF-Tris-HCl buffer. The complexes are efficient binders to calf thymus DNA. They are synthetic chemical nucleases in the presence of thiol or H₂O₂, forming hydroxyl radicals. The photoactive complexes are cleavers of pUC19 DNA in visible light, forming hydroxyl radicals. Complexes 2-6 show photocytotoxicity in HeLa cancer cells, giving IC₅₀ values of 4.7, 10.2, 1.3, 4.8, and 4.3 μ M, respectively, in visible light with the appearance of apoptotic bodies. The complexes also show photocytotoxicity in MCF-7 cancer cells. Nuclear chromatin cleavage has been observed with acridine orange/ethidium bromide (AO/EB) dual staining with complex 4 in visible light. The complexes induce caspase-independent apoptosis in the HeLa cells.