title: Synthesis, structure, and DNA cleavage properties of copper(II) complexes of 1,4,7-triazacyclononane ligands featuring pairs of guanidine pendants.
abstract: Two new ligands, L(1) and L(2), have been prepared via N-functionalization of 1,4,7-triazacyclononane (tacn) with pairs of ethyl- or propyl-guanidine pendants, respectively. The X-ray crystal structure of [CuL(1)](ClO4)2 (C1) isolated from basic solution (pH 9) indicates that a secondary amine nitrogen from each guanidine pendants coordinates to the copper(II) center in addition to the nitrogen atoms in the tacn macrocycle, resulting in a five-coordinate complex with intermediate square-pyramidal/trigonal bipyramidal geometry. The guanidines adopt an unusual coordination mode in that their amine nitrogen nearest to the tacn macrocycle binds to the copper(II) center, forming very stable five-membered chelate rings. A spectrophotometric pH titration established the pK(app) for the deprotonation and coordination of each guanidine group to be 3.98 and 5.72, and revealed that [CuL(1)](2+) is the only detectable species present in solution above pH ∼ 8. The solution speciation of the CuL(2) complex (C2) is more complex, with at least 5 deprotonation steps over the pH range 4-12.5, and mononuclear and binuclear complexes coexisting. Analysis of the spectrophotometric data provided apparent deprotonation constants, and suggests that solutions at pH ∼ 7.5 contain the maximum proportion of polynuclear complexes. Complex C1 exhibits virtually no cleavage activity toward the model phosphate diesters, bis(p-nitrophenyl)phosphate (BNPP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP), while C2 exhibits moderate activity. For C2, the respective kobs values measured at pH 7.0 (7.24 (± 0.08) × 10(-5) s(-1) (BNPP at 50 °C) and 3.2 (± 0.3) × 10(-5) s(-1) (HPNPP at 25 °C)) are 40- and 10-times faster than [Cu(tacn)(OH2)2](2+) complex. Both complexes cleave supercoiled pBR 322 plasmid DNA, indicating that the guanidine pendants of [CuL(1)](2+) may have been displaced from the copper coordination sphere to allow for DNA binding and subsequent cleavage. The rate of DNA cleavage by C2 is twice that measured for [Cu(tacn)(OH2)2](2+), suggesting some degree of cooperativity between the copper center and guanidinium pendants in the hydrolysis of the phosphate ester linkages of DNA. A predominantly hydrolytic cleavage mechanism was confirmed through experiments performed either in the presence of various radical scavengers or under anaerobic conditions.
authors.affiliation: School of Chemistry, Monash University, Vic 3800, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Tjioe
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Joshi
authors.forename: Joël
authors.initials: J
authors.lastname: Brugger
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.forename: Leone
authors.initials: L
authors.lastname: Spiccia
mesh_terms: D000693:Anaerobiosis; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D053837:DNA Cleavage / Q000187:drug effects*; D004952:Esters / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry; D019791:Guanidine / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D009596:Nitrophenols / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D004952:Esters; D016166:Free Radical Scavengers; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D008024:Ligands; D009596:Nitrophenols; D010710:Phosphates; D017382:Reactive Oxygen Species; D012996:Solutions; C075712:1,4,7-triazacyclononane; C002887:bis(4-nitrophenyl)phosphate; D003300:Copper; D019791:Guanidine