title: Anticancer copper pyridine benzimidazole complexes: ROS generation, biomolecule interactions, and cytotoxicity.
abstract: The Cu(II) complex CuCl2(pbzH), pbzH=2-(2-pyridyl)benzimidazole, and derivatives modified at the non-coordinated nitrogen of the benzimidazole fragment, have been studied as anticancer agents. These compounds show promising cytotoxicity against A549 adenocarcinomic alveolar basal epithelial cells with IC50values in the range of 5-10μM. Importantly, this activity is higher than either CuCl2·2H2O or the individual ligands, demonstrating that ligand coordination to the Cu(II) centres of the complexes is required for full activity. Electron paramagnetic resonance (EPR) and UV-Vis spectroscopies were used to characterize the solution behaviour of the complexes. These studies demonstrate: (i) two types of solvated species in buffer, (ii) both coordinate and non-coordinate interactions with albumin, and (iii) weak interactions with DNA. Further DNA studies using agarose gel electrophoresis demonstrate strand cleavage by the complexes in the presence of ascorbate, which is mediated by reactive oxygen species (ROS). Through a fluorescence-based in vitro assay, intracellular ROS generation in the A549 cell line was observed; indicating that damage by ROS is responsible for the observed activity of the complexes.
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Prosser
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Saraci
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Phuc H
authors.initials: PH
authors.lastname: Le
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, British Columbia, V5A 1S6, Canada. Electronic address: cwalsby@sfu.ca.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Walsby
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056831:Coordination Complexes; D003603:Cytotoxins; D004273:DNA, Neoplasm; D011725:Pyridines; D017382:Reactive Oxygen Species; D003300:Copper; C031000:benzimidazole
keywords: Albumin; Anticancer; Copper; DNA; Reactive oxygen species