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

Abstract

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)₂(L)]ClO₄ (<b>1</b>-<b>6</b>), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in <b>1</b> and <b>4</b>), dipyrido[3,2-<i>d</i>:2',3'-<i>f</i>]quinoxaline (dpq in <b>2</b> and <b>5</b>), and dipyrido[3,2-<i>a</i>:2',3'-<i>c</i>]phenazine (dppz in <b>3</b> and <b>6</b>), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat^2-, in <b>1</b>-<b>3</b>) or esculetin (6,7-dihydoxycoumarin, esc^2-, in <b>4</b>-<b>6</b>), 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 <b>1</b> (as PF₆^- salt, <b>1a</b>) and <b>2</b> show distorted octahedral geometries around the cobalt(III) center formed by the set of N₄O₂ donor atoms. The low-spin and 1:1 electrolytic complexes <b>1</b>-<b>6</b> display a d-d transition around 700 nm. Complexes <b>4</b>-<b>6</b> with a coordinated esc^2- ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes <b>4</b>-<b>6</b> possessing a naturally occurring and photoactive esc^2- ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC₅₀ values while being much less toxic under dark conditions. Control complexes <b>1</b>-<b>3</b> possessing the photoinactive cat^2- 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 <b>6</b> 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 <b>6</b> binds with the greatest affinity. Complex <b>6</b> 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 <b>6</b> showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.