Mitochondrial selectivity and remarkable photocytotoxicity of a ferrocenyl neodymium(iii) complex of terpyridine and curcumin in cancer cells

Abstract

A series of four novel neodymium(III) complexes of the formulation [Nd(R-tpy)(O–O)(NO₃)₂] (1–4), where R-tpy is 4′-phenyl-2,2′:6′,2′′-terpyridine (Ph-tpy; 1, 2) and 4′-ferrocenyl-2,2′:6′,2′′-terpyridine (Fc-tpy; 3, 4); O–O is the conjugate base of acetylacetone (Hacac; 1, 3) or curcumin (Hcurc; 2, 4), are synthesized and characterized. The single crystal structure of 1 shows that the complex is a discrete mononuclear species with the Nd(III) centre in a nine coordinate environment provided by a set of O₆N₃ donor atoms. Complexes 1 and 3 having the simple acac ligand are prepared as control compounds. Complex 4, possessing an appended ferrocenyl (Fc) and the curcumin moiety, is remarkably photocytotoxic to HeLa and MCF-7 cancer cells in visible light giving respective IC₅₀ values of 0.7 μM and 2.1 μM while being significantly less toxic to MCF-10A normal cells (IC₅₀ = 34 μM) and in the dark (IC₅₀ > 50 μM). The phenyl appended complex 2, lacking a ferrocenyl moiety, is significantly less toxic to both the cell lines when compared with 4. Complexes 1 and 3, lacking the photoactive curcumin moiety, do not show any apparent toxicity both in light and in the dark. The cell death is apoptotic in nature and is mediated by the light-induced formation of reactive oxygen species (ROS). Fluorescence imaging experiment with HeLa cells reveals mitochondrial accumulation of complex 4 within 4 h of incubation. The complexes bind to calf thymus (ct) DNA with moderate affinity giving K_b values in the range of 10⁴–10⁵ M⁻¹. The curcumin complexes 2 and 4 cleave plasmid supercoiled DNA to its nicked circular form in visible light via¹O2 and ˙OH pathways. The presence of the ferrocenyl moiety is likely to be responsible for the enhanced cellular uptake and photocytotoxicity of complex 4. Thus, the mitochondria targeting complex 4, being remarkably cytotoxic in light but non-toxic in the dark and to normal cells, is a potential candidate for photochemotherapeutic applications.