Mechanistic studies on DNA damage by minor groove binding copper–phenanthroline conjugates

Copper–phenanthroline complexes oxidatively damage and cleave nucleic acids. Copper bis-phenanthroline and copper complexes of mono- and bis-phenanthroline conjugates are used as research tools for studying nucleic acid structure and binding interactions. The mechanism of DNA oxidation and cleavage by these complexes was examined using two copper–phenanthroline conjugates of the sequence-specific binding molecule, distamycin. The complexes contained either one or two phenanthroline units that were bonded to the DNA-binding domain through a linker via the 3-position of the copper ligand. A duplex containing independently generated 2-deoxyribonolactone facilitated kinetic analysis of DNA cleavage. Oxidation rate constants were highly dependent upon the ligand environment but rate constants describing elimination of the alkali-labile 2-deoxyribonolactone intermediate were not. Rate constants describing DNA cleavage induced by each molecule were 11–54 times larger than the respective oxidation rate constants. The experiments indicate that DNA cleavage resulting from β-elimination of 2-deoxyribonolactone by copper–phenanthroline complexes is a general mechanism utilized by this family of molecules. In addition, the experiments confirm that DNA damage mediated by mono- and bis-phenanthroline copper complexes proceeds through distinct species, albeit with similar outcomes.

[1]  V. Lynch,et al.  Large pKa Shifts of α‐Carbon Acids Induced by Copper(II) Complexes , 2005 .

[2]  J. Stubbe,et al.  Bleomycins: towards better therapeutics , 2005, Nature Reviews Cancer.

[3]  K. Karlin,et al.  Changing selectivity of DNA oxidation from deoxyribose to Guanine by ligand design and a new binuclear copper complex. , 2005, Journal of the American Chemical Society.

[4]  M. Greenberg,et al.  Repair of oxidized abasic sites by exonuclease III, endonuclease IV, and endonuclease III. , 2004, Biochemistry.

[5]  B. Eipper,et al.  Oxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Spectroscopic definition of the resting sites and the putative CuIIM-OOH intermediate. , 2004, Biochemistry.

[6]  E. Solomon,et al.  Oxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Reaction mechanism and role of the noncoupled nature of the active site. , 2004, Journal of the American Chemical Society.

[7]  J. Klinman,et al.  Evidence That Dioxygen and Substrate Activation Are Tightly Coupled in Dopamine β-Monooxygenase , 2003, Journal of Biological Chemistry.

[8]  Miaoli Zhu,et al.  Crystal structure and nuclease activity of mono(1,10-phenanthroline) copper complex. , 2003, Journal of inorganic biochemistry.

[9]  M. Nethaji,et al.  Synthesis, crystal structure, and nuclease activity of planar mono-heterocyclic base copper(II) complexes. , 2003, Journal of inorganic biochemistry.

[10]  Daniel L Cole,et al.  Site‐specific DNA cleavage of synthetic NarL sites by an engineered Escherichia coli NarL protein–1,10‐phenanthroline cleaving agent , 2002, Protein science : a publication of the Protein Society.

[11]  B. Meunier,et al.  Acridine conjugates of 3-clip-phen: influence of the linker on the synthesis and the DNA cleavage activity of their copper complexes. , 2002, Bioconjugate chemistry.

[12]  M. Greenberg,et al.  A minor groove binding copper-phenanthroline conjugate produces direct strand breaks via beta-elimination of 2-deoxyribonolactone. , 2002, Journal of the American Chemical Society.

[13]  K. Karlin,et al.  Targeted strand scission of DNA substrates by a tricopper(II) coordination complex. , 2002, Journal of the American Chemical Society.

[14]  K. Karlin,et al.  Efficient and specific strand scission of DNA by a dinuclear copper complex: comparative reactivity of complexes with linked tris(2-pyridylmethyl)amine moieties. , 2002, Journal of the American Chemical Society.

[15]  J. I. Brauman,et al.  Conformation-dependent reaction thermochemistry: study of lactones and lactone enolates in the gas phase. , 2002, Journal of the American Chemical Society.

[16]  K. Karlin,et al.  Recognition and strand scission at junctions between single- and double-stranded DNA by a trinuclear copper complex. , 2001, Journal of the American Chemical Society.

[17]  J. Trauger,et al.  Footprinting methods for analysis of pyrrole-imidazole polyamide/DNA complexes. , 2001, Methods in enzymology.

[18]  C. Burrows,et al.  Mechanisms of DNA cleavage by copper complexes of 3-clip-phen and of its conjugate with a distamycin analogue. , 2000, Nucleic acids research.

[19]  C. Burrows,et al.  Targeting the DNA cleavage activity of copper phenanthroline and clip-phen to A.T tracts via linkage to a poly-N-methylpyrrole. , 2000, Bioconjugate chemistry.

[20]  H. Sugiyama,et al.  Mechanism of DNA Strand Scission Induced by (1,10-Phenanthroline)copper Complex: Major Direct DNA Cleavage Is Not through 1‘,2‘-Dehydronucleotide Intermediate nor β-Elimination of Forming Ribonolactone , 2000 .

[21]  M. Greenberg,et al.  The reactivity of the 2-deoxyribonolactone lesion in single-stranded DNA and its implication in reaction mechanisms of DNA damage and repair. , 1999, Nucleic acids research.

[22]  J. Chin,et al.  Rapid Hydrolysis of 2‘,3‘-cAMP with a Cu(II) Complex: Effect of Intramolecular Hydrogen Bonding on the Basicity and Reactivity of a Metal-Bound Hydroxide , 1999 .

[23]  M. Greenberg,et al.  Kinetics and Stereoselectivity of Thiol Trapping of Deoxyuridin-1‘-yl in Biopolymers and Their Relationship to the Formation of Premutagenic α-Deoxynucleotides , 1999 .

[24]  T. Tullius,et al.  DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Greenberg,et al.  DNA damage induced via independent generation of the radical resulting from formal hydrogen atom abstraction from the C1'-position of a nucleotide , 1998, Chemistry & biology.

[26]  D. Yoo,et al.  Release of Superoxide from Nucleoside Peroxyl Radicals, a Double-Edged Sword? , 1998 .

[27]  T. Tullius,et al.  Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety. , 1998, Chemical reviews.

[28]  R. Burger.  Cleavage of Nucleic Acids by Bleomycin. , 1998, Chemical reviews.

[29]  M. Greenberg,et al.  Model Studies Indicate That Copper Phenanthroline Induces Direct Strand Breaks via β-Elimination of the 2‘-Deoxyribonolactone Intermediate Observed in Enediyne Mediated DNA Damage , 1998 .

[30]  A. Hamilton,et al.  CATALYSIS OF PHOSPHODIESTER TRANSESTERIFICATION BY CU(II)-TERPYRIDINE COMPLEXES WITH PERIPHERAL PENDENT BASE GROUPS : IMPLICATIONS FOR THE MECHANISM , 1997 .

[31]  M. Meijler,et al.  Chemical Mechanism of DNA Scission by (1,10-Phenanthroline)copper. Carbonyl Oxygen of 5-Methylenefuranone Is Derived from Water , 1997 .

[32]  R. C. Johnson,et al.  Identification of new Fis binding sites by DNA scission with Fis-1,10-phenanthroline-copper(I) chimeras. , 1996, Biochemistry.

[33]  R. Landgraf,et al.  Nucleic acid chemistry of the cuprous complexes of 1,10-phenanthroline and derivatives. , 1996, Metal ions in biological systems.

[34]  T. Tullius,et al.  What Species Is Responsible for Strand Scission in the Reaction of [FeIIEDTA]2- and H2O2 with DNA? , 1995 .

[35]  Y. Tor,et al.  Simple one-step synthesis of 3-bromo- and 3,8-dibromo-1,10-phenanthroline: Fundamental building blocks in the design of metal chelates , 1995 .

[36]  J. Chin,et al.  Rapid Hydrolysis of RNA with a CuII Complex , 1995 .

[37]  R. Ebright,et al.  High-specificity DNA cleavage agent: design and application to kilobase and megabase DNA substrates. , 1994, Science.

[38]  C. Pan,et al.  DNA‐binding proteins as site‐specific nucleases , 1994, Molecular microbiology.

[39]  A. McMahon,et al.  DNA affinity cleaving analysis of homeodomain-DNA interaction: identification of homeodomain consensus sites in genomic DNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T. W. Bruice,et al.  Targeted Chemical Nucleases , 1993 .

[41]  P. Dervan,et al.  Adenine-specific DNA chemical sequencing reaction. , 1987, Methods in enzymology.

[42]  J. Veal,et al.  The influence of reducing agent and 1,10-phenanthroline concentration on DNA cleavage by phenanthroline + copper. , 1991, Nucleic acids research.

[43]  L. Casella,et al.  Model monooxygenase reactivity by binuclear two-coordinate copper(I) complexes extends to new ligand systems containing nitrogen and sulphur donors , 1991 .

[44]  D. Wemmer,et al.  Binding modes of distamycin A with d(CGCAAATTTGCG)2 determined by two-dimensional NMR , 1990 .

[45]  D. Sigman,et al.  Chemical nucleases. , 1990, Biochemistry.

[46]  T. Larsen,et al.  Nuclease activity of 1,10-phenanthroline―copper: kinetic mechanism , 1989 .

[47]  D. Sigman,et al.  Sequence-specific scission of RNA by 1,10-phenanthroline-copper linked to deoxyoligonucleotides , 1988 .

[48]  J. Stubbe,et al.  Mechanisms of bleomycin-induced DNA degradation , 1987 .

[49]  D. Sigman,et al.  Chemical conversion of a DNA-binding protein into a site-specific nuclease. , 1987, Science.

[50]  D. Sigman,et al.  Nuclease activity of 1,10-phenanthroline-copper ion. Chemistry of deoxyribose oxidation , 1987 .

[51]  N. Nazhat,et al.  Kinetics and mechanism of the reaction of the bis(1,10-phenanthroline)copper(I) ion with hydrogen peroxide in aqueous solution , 1987 .

[52]  D. Sigman,et al.  Nuclease activity of 1,10-phenanthroline-copper ion: reaction with CGCGAATTCGCG and its complexes with netropsin and EcoRI. , 1986, Biochemistry.

[53]  D. Sigman.  Nuclease activity of 1,10-phenanthroline-copper ion , 1986 .

[54]  P. Dervan.  Design of sequence-specific DNA-binding molecules. , 1986, Science.

[55]  D. R. Graham,et al.  Oxygen-dependent cleavage of DNA by the 1,10-phenanthroline . cuprous complex. Inhibition of Escherichia coli DNA polymerase I. , 1979, The Journal of biological chemistry.

[56]  P. Kroneck,et al.  Model studies on the coordination of copper in enzymes. IV. Structure and stability of cuprous complexes with sulfur-containing ligands , 1976 .