title: The phosphate clamp: sequence selective nucleic acid binding profiles and conformational induction of endonuclease inhibition by cationic Triplatin complexes.
abstract: The substitution-inert polynuclear platinum(II) complex (PPC) series, [{trans-Pt(NH3)2(NH2(CH2)nNH3)}2-μ-(trans-Pt(NH3)2(NH2(CH2)nNH2)2}](NO3)8, where n = 5 (AH78P), 6 (AH78 TriplatinNC) and 7 (AH78H), are potent non-covalent DNA binding agents where nucleic acid recognition is achieved through use of the 'phosphate clamp' where the square-planar tetra-am(m)ine Pt(II) coordination units all form bidentate N-O-N complexes through hydrogen bonding with phosphate oxygens. The modular nature of PPC-DNA interactions results in high affinity for calf thymus DNA (Kapp ∼5 × 10(7) M(-1)). The phosphate clamp-DNA interactions result in condensation of superhelical and B-DNA, displacement of intercalated ethidium bromide and facilitate cooperative binding of Hoechst 33258 at the minor groove. The effect of linker chain length on DNA conformational changes was examined and the pentane-bridged complex, AH78P, was optimal for condensing DNA with results in the nanomolar region. Analysis of binding affinity and conformational changes for sequence-specific oligonucleotides by ITC, dialysis, ICP-MS, CD and 2D-(1)H NMR experiments indicate that two limiting modes of phosphate clamp binding can be distinguished through their conformational changes and strongly suggest that DNA condensation is driven by minor-groove spanning. Triplatin-DNA binding prevents endonuclease activity by type II restriction enzymes BamHI, EcoRI and SalI, and inhibition was confirmed through the development of an on-chip microfluidic protocol.
authors.affiliation: School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors.forename: Andreea
authors.initials: A
authors.lastname: Prisecaru
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.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Kipping
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Peterson
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Qu
authors.affiliation: School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland andrew.kellett@dcu.ie.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kellett
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D001483:Base Sequence; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D059371:DNA, B-Form / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010710:Phosphates / Q000737:chemistry; D012343:RNA, Transfer / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D059371:DNA, B-Form; D004791:Enzyme Inhibitors; D008024:Ligands; D009944:Organoplatinum Compounds; D010710:Phosphates; D004247:DNA; D012343:RNA, Transfer; C427203:calf thymus DNA; D015252:Deoxyribonucleases, Type II Site-Specific