title: Copper phenanthrene oxidative chemical nucleases.
abstract: Here we report the synthesis and isolation of a series of bis-chelate Cu(2+) phenanthroline-phenazine cationic complexes of [Cu(DPQ)(Phen)](2+), [Cu(DPPZ)(Phen)](2+), and [Cu(DPPN)(Phen)](2+) (where Phen = 1,10-phenanthroline, DPQ = dipyridoquinoxaline, DPPZ = dipyridophenazine, and DPPN = benzo[i]dipyridophenazine). These compounds have enhanced DNA recognition relative to the well-studied chemical nuclease, [Cu(Phen)2](2+) (bis-Phen), with calf thymus DNA binding constants of DPQ and DPPZ agents (∼10(7) M(bp)(-1)) being the highest currently known for Cu(2+) phenanthrene compounds. Complex DNA binding follows DPQ ≈ DPPZ > DPPN > bis-Phen, with fluorescence quenching and thermal melting experiments on poly[d(A-T)2] and poly[d(G-C)2] supporting intercalation at both the minor and major groove. Phenazine complexes, however, show enhanced targeting and oxidative cleavage on cytosine-phosphate-guanine-rich DNA and have comparable in vitro cytotoxicity toward the cisplatin-resistant ovarian cancer line, SKOV3, as the clinical oxidative DNA-damaging drug doxorubicin (Adriamycin). In this study we also describe how a novel "on-chip" method devised for the Bioanalyser 2100 was employed to quantify double-stranded DNA damage, with high precision, by the complex series on pUC19 DNA (49% A-T, 51% G-C). Both DPQ and bis-Phen complexes are highly efficient oxidizers of pUC19, with DPQ being the most active of the overall series. It is apparent, therefore, that oxidative chemical nuclease activity on homogeneous canonical DNA is not entirely dependent on dynamic nucleotide binding affinity or intercalation, and this observation is corroborated through catalytic interactions with the superoxide anion radical and Fenton breakdown of hydrogen peroxide.
authors.affiliation: School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University , Glasnevin, Dublin 9, Ireland.
authors.forename: Zara
authors.initials: Z
authors.lastname: Molphy
authors.forename: Andreea
authors.initials: A
authors.lastname: Prisecaru
authors.forename: Creina
authors.initials: C
authors.lastname: Slator
authors.forename: Niall
authors.initials: N
authors.lastname: Barron
authors.forename: Malachy
authors.initials: M
authors.lastname: McCann
authors.forename: John
authors.initials: J
authors.lastname: Colleran
authors.forename: Deepak
authors.initials: D
authors.lastname: Chandran
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gathergood
authors.forename: Andrew
authors.initials: A
authors.lastname: Kellett
mesh_terms: D000818:Animals; D002417:Cattle; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D005453:Fluorescence; D006801:Humans; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D009942:Organometallic Compounds; D010616:Phenanthrenes; C031181:phenanthrene; D003300:Copper; D004247:DNA; C427203:calf thymus DNA