Structure−Activity Relationship of Photocytotoxic Iron(III) Complexes of Modified Dipyridophenazine Ligands

Abstract

Iron(III) complexes [FeL(B)] (1-5) of a tetradentate trianionic phenolate-based ligand (L) and modified dipyridophenazine bases (B), namely, dipyrido-6,7,8,9-tetrahydrophenazine (dpqC in 1), dipyrido[3,2-a:2',3'-c]phenazine-2-carboxylic acid (dppzc in 2), dipyrido[3,2-a:2',3'-c]phenazine-11-sulfonic acid (dppzs in 3), 7-aminodipyrido[3,2-a:2',3'-c]phenazine (dppza in 4) and benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn in 5), have been synthesized and their photocytotoxic properties studied along with their dipyridophenazine analogue (6). The complexes have a five electron paramagnetic iron(III) center, and the Fe(III)/Fe(II) redox couple appears at about -0.69 V versus SCE in DMF-0.1 M TBAP. The physicochemical data also suggest that the complexes possess similar structural features as that of its parent complex [FeL(dppz)] with FeO3N3 coordination in a distorted octahedral geometry. The DNA-complex and protein-complex interaction studies have revealed that the complexes interact favorably with the biomolecules, the degree of which depends on the nature of the substituents present on the dipyridophenazine ring. Photocleavage of pUC19 DNA by the complexes has been studied using visible light of 476, 530, and 647 nm wavelengths. Mechanistic investigations with inhibitors show formation of HO(•) radicals via a photoredox pathway. Photocytotoxicity study of the complexes in HeLa cells has shown that the dppn complex (5) is highly active in causing cell death in visible light with sub micromolar IC(50) value. The effect of substitutions and the planarity of the phenazine moiety on the cellular uptake are quantified by determining the total cellular iron content using the inductively coupled plasma-optical emission spectrometry (ICP-OES) technique. The cellular uptake increases marginally with an increase in the hydrophobicity of the dipyridophenazine ligands whereas complex 3 with dppzs shows very high uptake. Insights into the cell death mechanism by the dppn complex 5, obtained through DAPI nuclear staining in HeLa cells, reveal a rapid programmed cell death mechanism following photoactivation of complex 5 with visible light. The effect of substituent on the DNA photocleavage activity of the complexes has been rationalized from the theoretical studies.

Synthesis, DNA binding and docking studies of copper(II) complexes containing modified phenanthroline ligands

“…Porphyrin-, phthalocyanine-and other macrocyclic-based photodynamic therapy (PDT) agents have been designed to show strong correlations between the hydrophobicity of the PDT agents and their therapeutic activity [10][11][12][13][14][15][16]. Among metal-based PDT agents, rhodium, ruthenium and iron complexes show strong dependence of biological activity on their molecular structures [17][18][19][20]. Extended planar aromatic ring in the ligands allows better intercalation with DNA [21].…”

Synthesis and characterization of cobalt(II), nickel(II) and copper(II)-based potential photosensitizers: Evaluation of their DNA binding profile, cleavage and photocytotoxicity

“…Cisplatin is a well-known non-PDT model complex, therefore under the same experimental conditions; it was evaluated as a reference metallodrug [109,111]. No reduction in the cell viability was observed on photoexposure of the cells in the absence of the complex.…”

Synthesis, Characterization, and Biological Evaluation of Red-Absorbing Fe(II) Polypyridine Complexes

“…To tackle metal, it is anticipated to have a reduced metal-induced cellular toxicity [34,35] in comparison to other metal-based complexes. Chakravarty and co-workers have already reported several Fe(III)-based complexes with a dipyrido[3,2-d:2 ,3 -f]quinoxaline [35][36][37] or a dipicolylamine [34,[38][39][40][41][42][43][44][45] moiety as effective PSs. As an impressive example, the Fe(III) complexes 1 was prepared with a dipicolylamine ligand combined with an anthracenyl moiety, which is able to intercalate in the DNA, and a catechol ligand, which promotes an intense ligand-to-metal charge-transfer band in the near IR window (Figure 1).…”