Remarkable visible light-triggered cytotoxicity of mitochondria targeting mixed-ligand cobalt(iii) complexes of curcumin and phenanthroline bases binding to human serum albumin

Abstract

Six new mixed-ligand cobalt(III) complexes of formulation [Co(N–N)₂(O–O)](ClO₄)₂ (1–6), where N–N is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 5, 6), O–O is acetylacetonate (acac in 1, 3, 5) or curcumin (bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, cur in 2, 4, 6), have been synthesized and characterized. The X-ray crystal structures of complex 1 (as PF₆⁻ salt, 1a) and 3 show distorted octahedral geometries formed by the CoN₄O₂ core. The complexes 1, 3 and 5 having the simple acac ligand are prepared as control species to understand the role of curcumin. The optimized geometries and the frontier orbitals of the curcumin complexes 2, 4, and 6 are obtained from the DFT calculations. The complexes 2, 4, and 6 having the photoactive curcumin moiety display an absorption band in the visible region near 420 nm and show remarkable photocytotoxicity in HeLa cancer cells with respective IC₅₀ values of 7.4 μM, 5.1 μM and 1.6 μM while being much less toxic in dark. MTT assay using complex 6 shows that it is not significantly photocytotoxic to MCF-10A normal cells. The control complexes having the acac ligand are non-toxic both in the presence and absence of light. The cell death is apoptotic in nature and triggered by the photogeneration of reactive oxygen species. Fluorescence imaging experiments on HeLa cells reveals that complex 6 accumulated primarily inside the mitochondria. Human serum albumin (HSA) binding experiments show that the complexes bind HSA with good affinity, but 6 binds with the highest affinity, with a K_b value of 9.8 × 10⁵ M⁻¹. Thus, complex 6 with its negligible toxicity in the dark and in normal cells but remarkable toxicity in visible light holds significant photochemotherapeutic potential.