title: Efficient plasmid DNA cleavage by copper(II) complexes of 1,4,7-triazacyclononane ligands featuring xylyl-linked guanidinium groups.
abstract: Three new metal-coordinating ligands, L(1), L(2), and L(3), have been prepared by appending o-, m-, and p-xylylguanidine pendants, respectively, to one of the nitrogen atoms of 1,4,7-triazacyclononane (tacn). The copper(II) complexes of these ligands are able to accelerate cleavage of the P-O bonds within the model phosphodiesters bis(p-nitrophenyl)phosphate (BNPP) and [2-(hydroxypropyl)-p-nitrophenyl]phosphate (HPNPP), as well as supercoiled pBR 322 plasmid DNA. Their reactivity toward BNPP and HPNPP is not significantly different from that of the nonguanidinylated analogues, [Cu(tacn)(OH(2))(2)](2+) and [Cu(1-benzyl-tacn)(OH(2))(2)](2+), but they cleave plasmid DNA at considerably faster rates than either of these two complexes. The complex of L(1), [Cu(L(1)H(+))(OH(2))(2)](3+), is the most active of the series, cleaving the supercoiled plasmid DNA (form I) to the relaxed circular form (form II) with a k(obs) value of (2.7 ± 0.3) × 10(-4) s(-1), which corresponds to a rate enhancement of 22- and 12-fold compared to those of [Cu(tacn)(OH(2))(2)](2+) and [Cu(1-benzyl-tacn)(OH(2))(2)](2+), respectively. Because of the relatively fast rate of plasmid DNA cleavage, an observed rate constant of (1.2 ± 0.5) × 10(-5) s(-1) for cleavage of form II DNA to form III was also able to be determined. The X-ray crystal structures of the copper(II) complexes of L(1) and L(3) show that the distorted square-pyramidal copper(II) coordination sphere is occupied by three nitrogen atoms from the tacn ring and two chloride ions. In both complexes, the protonated guanidinium pendants extend away from the metal and form hydrogen bonds with solvent molecules and counterions present in the crystal lattice. In the complex of L(1), the distance between the guanidinium group and the copper(II) center is similar to that separating the adjacent phosphodiester groups in DNA (ca. 6 Å). The overall geometry of the complex is also such that if the guanidinium group were to form charge-assisted hydrogen-bonding interactions with a phosphodiester group, a metal-bound hydroxide would be well-positioned to affect the nucleophilic attack on the neighboring phosphodiester linkage. The enhanced reactivity of the complex of L(1) at neutral pH appears to also be, in part, due to the relatively low pK(a) of 6.4 for one of the coordinated water molecules.
authors.affiliation: School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Tjioe
authors.forename: Anja
authors.initials: A
authors.lastname: Meininger
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Joshi
authors.forename: Leone
authors.initials: L
authors.lastname: Spiccia
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
mesh_terms: D056831:Coordination Complexes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D053837:DNA Cleavage / Q000187:drug effects*; D004262:DNA Restriction Enzymes / Q000737:chemistry / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D019791:Guanidine / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000378:metabolism; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism*; D011522:Protons; D014867:Water
chemical_list: D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D008024:Ligands; D009596:Nitrophenols; D011522:Protons; D014867:Water; C075712:1,4,7-triazacyclononane; C002887:bis(4-nitrophenyl)phosphate; D003300:Copper; D004247:DNA; D004262:DNA Restriction Enzymes; D019791:Guanidine