title: Potent anticancer activity of photo-activated oxo-bridged diiron(III) complexes.
abstract: Cancer-specific anticancer drugs are still an elusive goal. Using light as the temporal control to generate cytotoxic species from photo-activated prodrug in the presence or absence of molecular oxygen has shown potential application targeted chemotherapy as in photodynamic therapy (PDT). In the present work we explored the chemistry of several photo-active (μ-oxo)diiron(III) complexes of the following formulation [{Fe(μ-O) (L-his)(B)}2](ClO4)2(1a-1c), [Fe2(μ-O)(H2O)2B4](ClO4)4(2b, 2c) and [Fe2(μ-O)(μ-O2CMe)B4](ClO4)3(3b, 3c), L-his = l-histidine, B is 2,2'-bipyridine, 1,10-phenanthroline (phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) complexes for tumor-specific anticancer activity. Facile redox chemistry and photochemical aspects of the complexes prompted us to investigate the cytotoxic as well as the photo-activated cytotoxic properties of the complexes to the cancer cells. In the present investigation we explored the cancer-specific condition of excess concentration of H2O2for our approach to targeted chemotherapy. Cytotoxic effect of the complexes to the cancer cells was found to be significantly higher than in normal cells indicating tumor-specific anticancer activity of the complexes. Cytotoxic effect was even more pronounced when the cancer cells treated with the complexes were exposed to the visible light (400-700 nm). There was >12 fold increase in cytotoxicity of the photoactivated complexes in cancer cells (MCF-7) in comparison to the normal cells (MCF-10a). We have defined a factor viz. cancer cell specificity factor (f) describing the targeted photochemotherapeutic effect of the complexes at their specific concentration. The factor (f) > 1 indicated the cancer cell specificity of the complexes, while f > 2.5 for the complexes under the visible light exposure suggested photodynamic effect. DCFDA assay indicated the presence of excess of ROS in the treated HeLa cells. ROS concentration was found to increase even more on visible light exposure. Increased ROS in the cancer cells disturb the cellular redox mechanism inducing oxidative stress to lethality. Decarboxylation of photo-activated diiron(III) complexes generate OH radical responsible for cell death. Overall, the high efficacy and selectivity of the (μ-oxo)diiron(III) complexes potentially make them suitable for in vivo applications and extensive testing toward transfer into the clinical arena.
authors.affiliation: Department of Chemistry, National Institute of Technology, Manipur, Langol, 795004, Imphal, Manipur, India.
authors.forename: S Binita
authors.initials: SB
authors.lastname: Chanu
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Samya
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, National Institute of Technology, Manipur, Langol, 795004, Imphal, Manipur, India. Electronic address: mithunroy@nitmanipur.ac.in.
authors.forename: Mithun
authors.initials: M
authors.lastname: Roy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide; D058085:Iron Compounds / Q000528:radiation effects; D008027:Light; D010084:Oxidation-Reduction / Q000187:drug effects; D010778:Photochemotherapy / Q000379:methods*; D011355:Prodrugs / Q000737:chemistry / Q000528:radiation effects; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D058085:Iron Compounds; D011355:Prodrugs; D006861:Hydrogen Peroxide
keywords: Apoptosis; Cancer-specific cytotoxicity; Oxo-bridged diiron(III) complexes; Photo-activated chemotherapy; ROS generation