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 (1–6), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1 and 4), dipyrido­[3,2-d:2′,3′-f]­quinoxaline (dpq in 2 and 5), and dipyrido­[3,2-a:2′,3′-c]­phenazine (dppz in 3 and 6), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat2–, in 1–3) or esculetin (6,7-dihydoxycoumarin, esc2–, in 4–6), 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 1 (as PF6 – salt, 1a) and 2 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 1–6 display a d–d transition around 700 nm. Complexes 4–6 with a coordinated esc2– ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes 4–6 possessing a naturally occurring and photoactive esc2– 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 1–3 possessing the photoinactive cat2– 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 6 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 6 binds with the greatest affinity. Complex 6 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 6 showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.

Recent Advances on the Development of Early Transition Metal Complexes for Photo‐Assisted Cytotoxicity Applications

“…The complexes showed remarkable light-induced toxicity with negligible dark toxicity. [92] Vanadium complexes also produced hydroxyl radical upon irradiation as shown by Chakravarty and his group by synthesizing four oxovanadium (IV) complexes with curcuminoids (55-58). The Cytotoxicity was assessed in HeLa, HepG2 and 3T3 cells in the dark as well as in visible light.…”

A Mini-Review: Recent Advances in Coumarin-Metal Complexes With Biological Properties

“…Worth noting are cobalt (III) complexes [Co(B) 2 (L)]ClO 4 9-11 ( Table 1 ) prepared by Sakar and co-workers in a two-step procedure, starting from N , N -donor bases: 1,10-phenanthroline ( phen ), dipyrido [3,2-days:2′,3′- f ]quinoxaline ( dpq ) or dipyrido [3,2- a :2′,3′- c ]phenazine base ( dppz ) and naturally occurring esculetin (6,7-dihydroxycoumarin) as dianionic O , O -donor, as well as cobalt (II) chloride and sodium perchlorate in the presence of triethylamine ( Sarkar et al, 2021 ). These new complexes, due to their high visible light-triggered cytotoxicity against cervical cancer cell line (HeLa) and human breast cancer cell line (MCF-7), represent an interesting example of potent next-generation photochemotherapeutics.…”

Density Functional Theory-Guided Photo-Triggered Anticancer Activity of Curcumin-Based Zinc(II) Complexes

“…It has been established that the metal complexation of curcumin increases its stability and bioavailability. − Moreover, curcumin is reported as a good photosensitizer due to its efficient singlet oxygen generation ability under visible light . Therefore, in recent years, several curcumin-based metal complexes have been reported for PDT. − ,− Several curcumin complexes of V­(IV), Fe­(III), Co­(II), Co­(III), Pt­(II), Ru­(II), Ir­(III), Os­(II), Rh­(III), etc. are explored as photosensitizers for PDT application, but the example of Zn­(II)-curcumin complexes in PDT is very rare. − ,− To the best of our knowledge, Chakraborty et al reported the only Zn­(II)-curcumin complex with BODIPY as a pendant for PDT activity .…”

“…Therefore, in recent years, several curcumin-based metal complexes have been reported for PDT. − ,− Several curcumin complexes of V­(IV), Fe­(III), Co­(II), Co­(III), Pt­(II), Ru­(II), Ir­(III), Os­(II), Rh­(III), etc. are explored as photosensitizers for PDT application, but the example of Zn­(II)-curcumin complexes in PDT is very rare. − ,− To the best of our knowledge, Chakraborty et al reported the only Zn­(II)-curcumin complex with BODIPY as a pendant for PDT activity . Thus, although curcumin-based Zn­(II) complexes have been well-explored as cancer chemotherapeutics, their use as photosensitizers for PDT has not been well-explored.…”