Mixed-Ligand Cobalt(III) Complexes of a Naturally Occurring Coumarin and Phenanthroline Bases as Mitochondria-Targeted Dual-Purpose Photochemotherapeutics.

The bioessential nature of cobalt and the rich photochemistry of its coordination complexes can be exploited to develop potential next-generation photochemotherapeutics. A series of six novel mixed-ligand cobalt(III) complexes of the formulation [Co(B)(L)]ClO (-), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in and ), dipyrido[3,2-:2',3'-]quinoxaline (dpq in and ), and dipyrido[3,2-:2',3'-]phenazine (dppz in and ), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat, in -) or esculetin (6,7-dihydoxycoumarin, esc, in -), have been prepared and characterized, and their light-triggered cytotoxicity has been studied in cancer cells. The single-crystal X-ray diffraction structures of complexes (as PF salt, ) and show distorted octahedral geometries around the cobalt(III) center formed by the set of NO donor atoms. The low-spin and 1:1 electrolytic complexes - display a d-d transition around 700 nm. Complexes - with a coordinated esc ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes - possessing a naturally occurring and photoactive esc ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC values while being much less toxic under dark conditions. Control complexes - possessing the photoinactive cat ligand show significantly less cytotoxicity either in the presence of light or in the dark. The complex-induced cell death is apoptotic in nature caused by the formation of reactive oxygen species via a type 1 photoredox pathway. Fluorescence microscopy of HeLa cells treated with complex reveals mitochondrial localization of the complex. A significant decrease in the dark toxicity of free esculetin and dppz base is observed upon coordination to cobalt(III). Complexes bind to calf-thymus DNA with significant affinity, but binds with the greatest affinity. Complex efficiently photocleaves supercoiled DNA to its nicked circular form when irradiated with visible light via a photoredox type 1 pathway involving hydroxyl radicals (HO). Thus, complex showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.