title: Evaluation of complexation of metal-mediated DNA-binding drugs to oligonucleotides via electrospray ionization mass spectrometry.
abstract: The interactions of self-complementary oligonucleotides with a group of metal-mediated DNA-binding drugs, including chromomycin A(3), mithramycin and the novel compound UK-1, were examined via electrospray ionization quadrupole ion trap mass spectrometry. Both chromomycin and mithramycin were shown to bind preferentially to GC-rich oligonucleotide duplexes in a 2:1 drug:metal ratio, while UK-1 was shown to bind in a 1:1 drug:metal stoichiometric ratio without a strong sequence preference. These trends were observed in the presence of Co(2+), Ni(2+) and Zn(2+), with the exception that chromomycin-Zn(2+) complexes were not readily observed. The binding stoichiometries as well as the sequence specificities are in agreement with literature reports for solution studies. Binding selectivities and stabilities of the complexes were also probed using electrospray ionization mass spectrometry. Both of the GC-rich oligomers 5'-GCGCGC-3' and 5'-GCGCATGCGC-3' exhibited a binding preference for chromomycin over mithramycin in the presence of Co(2+) and Ni(2+). Energy-variable collisionally activated dissociation of the complexes was employed to determine the stabilities of the complexes. The relative metal-dependent binding energies were Ni(2+) > Zn(2+) > Co(2+) for UK-1-oligomer complexes and Ni(2+) > Co(2+) for both mithramycin and chromomycin complexes.
authors.affiliation: Department of Chemistry and Biochemistry and Division of Medicinal Chemistry and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Reyzer
authors.forename: J S
authors.initials: JS
authors.lastname: Brodbelt
authors.forename: S M
authors.initials: SM
authors.lastname: Kerwin
authors.forename: D
authors.initials: D
authors.lastname: Kumar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence; D001583:Benzoxazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D014128:Chromomycin A3 / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004214:Distamycins / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D008670:Metals / Q000378:metabolism*; D008970:Molecular Weight; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008926:Plicamycin / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013302:Streptomyces / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013696:Temperature; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D004214:Distamycins; D008670:Metals; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; C082787:UK 1; C030000:stallimycin; D004247:DNA; D014128:Chromomycin A3; D008926:Plicamycin