Kinetics of formation and stability of [Pt(dien)]2+ complexes with octamer and 14-mer DNA oligonucleotides containing a GG sequence.
Reaction of [Pt(dien)Cl]+ (1) with the 14-mer oligonucleotide 5'-d(ATACATGGTACATA) (I) gave rise to two major species which corresponded to the 5'-G and 3'-G platinated monofunctional adducts, and a minor amount of the bis-platinated adduct formed during the later stages of the reaction. The reaction of (1) with the related octamer 5'-d(ATA-CATGG) (II) was also investigated. Kinetic data obtained by HPLC showed that the 5'-G and 3'-G bases of the 14-mer oligonucleotide were platinated at similar rates: the second-order rate constant is 53 x 10(-2) M-1 s-1 at 298 K in 0.1 M NaClO4. However, the platination rate of 5'-G of the octamer (II) (k = 69 x 10(-2) M-1 s-1) was enhanced by a factor of three compared to the rate of platination at 3'-G (k = 22 x 10(-2) M-1 s-1). All the adducts were separated by HPLC and characterized by NMR spectroscopy, enzymatic digestion and MALDITOF mass spectrometry. 1H and 15N NMR shifts suggest that there are distinct conformational differences between 14-mer duplexes platinated at 5'-G (I5' ds) and 3'-G (I3' ds). Molecular mechanics modelling indicates that rotation around the Pt-N7 bond is more restricted in the case of the 5'-G adduct than in that of the 3'-G adduct. The binding of {Pt(dien)}2+ to 5'-GN7 and 3'-GN7 in the monofunctional adducts of (I) was shown to be reversible upon the addition of high concentrations of chloride ions.
Murdoch
P del S
Pdel S
Department of Chemistry, University of Edinburgh, UK.
Guo
Z
Z
Parkinson
J A
JA
Sadler
P J
PJ
D001483:Base Sequence; D002712:Chlorides / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013816:Thermodynamics
D002712:Chlorides; D018736:DNA Adducts; D009841:Oligonucleotides; C032799:chlorodiethylenetriamine platinum; D002945:Cisplatin