title: Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence.
abstract: Reactions of cis-[PtCl(NH(3))(CyNH(2))(OH(2))](+) (Cy=cyclohexyl) with thione-containing single-stranded oligonucleotides d(T(8)XT(8)) and d(XT(16)) (X=(s6)I or (s4)U) and the mononucleotides 4-thiouridine ((s4)UMP) and 6-mercaptoinosine ((s6)IMP) have been studied in aqueous solution at pH 4.1. The reaction kinetics was followed using HPLC methodology as a function of ionic strength in the interval 5.0 mM<or= I<or=300 mM. A two-fold kinetic preference for reaction with the (s6)I moiety over (s4)U is observed in both monomeric and oligomeric systems. The rate for adduct formation with the oligonucleotides d(T(8)XT(8)) and d(XT(16)) decreases with increasing ionic strength of the medium. The effect is most pronounced for adduct formation with the middle positions, e.g. for d(T(8)(s6)IT(8)): k(2,app)=370 M(-1 )s(-1) and 13 M(-1 )s(-1) at I=5.0 and 300 mM, respectively, and slightly less pronounced for adduct formation at the end positions, e.g. for d((s6)IT(16)): k(2,app)=130 M(-1 )s(-1) and 11 M(-1 )s(-1) at I=5.0 and 300 mM, respectively. Analysis of the salt dependence using the Brønsted-Debye-Hückel relationship shows that the reactions with the monomers are well described as an interaction between a monovalent cation and a monovalent anion. In contrast, a similar analysis of the oligonucleotide reactions indicates influence from polyelectrolyte effects. The results support a mechanism in which pre-association on the DNA surface precedes adduct formation, regardless of the exact location of the final binding site.
authors.affiliation: Inorganic Chemistry, Chemical Center, Lund University, P O Box 124, 221 00 Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Kjellström
authors.forename: Sofi K C
authors.initials: SK
authors.lastname: Elmroth
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018736:DNA Adducts / Q000096:biosynthesis / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D009994:Osmolar Concentration; D010472:Perchlorates / Q000737:chemistry; D017670:Sodium Compounds / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013868:Thioinosine / Q000737:chemistry* / Q000378:metabolism; D013871:Thiones / Q000737:chemistry*; D013891:Thiouridine / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018736:DNA Adducts; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; D010472:Perchlorates; D017670:Sodium Compounds; D013871:Thiones; D013891:Thiouridine; D013868:Thioinosine; C031068:sodium perchlorate