Reaction of DNA oligonucleotides with [Pt(dien)GSMe]2+ (GSMe = S-methylated glutathione) and cis-[Pt(NH3)2(GSMe)2]2+: evidence of oligonucleotide platination via sulfur-coordinated platinum intermediates.
To study the possibility of DNA platination via platinum-sulfur coordinated intermediates, the reactions of the complexes [Pt(dien)GSMe]2+ (GSMe=S-methylated glutathione) and cis-[Pt(NH3)2(GSMe)2]2+ with the synthetic oligonucleotides d(ATATGCATAT), d(ATTACCGGTAAT), and d(ATCCTATTTTTTTTAGGAT) have been investigated. The reactions were studied using FPLC, NMR, and mass spectrometry. It was found that the sulfur atom of the platinum-thioether adduct is substituted by these oligonucleotides. For the reactions with [Pt(dien)GSMe]2+ at 310 K, half-lives were determined to be t 1/2 =147+/-7 h for d(ATATGCATAT), t 1/2 =84+/-4 h) for d(ATTACCGGTAAT), and t 1/2 = 21+/-1 h for d(ATCCTATTTTTTTTAGGAT. This study clearly shows that it is indeed possible for oligonucleotides to be platinated via Pt-thioether coordinated intermediates. The rates at which such substitutions occur, however, makes it improbable that such a mechanism contributes significantly to the antitumor activity of cisplatin.
Teuben
J M
JM
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, The Netherlands.
Reedijk
J
J
D002845:Chromatography; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D006147:Guanine / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D010984:Platinum / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry
D018736:DNA Adducts; D009838:Oligodeoxyribonucleotides; D009944:Organoplatinum Compounds; D013440:Sulfides; C074168:chlorodiethylenetriamine platinum(II)-S-methyl-glutathione complex; C417703:diamminebis(S-methylglutathione)platinum(II); D010984:Platinum; D006147:Guanine; D013455:Sulfur; D005978:Glutathione; D002945:Cisplatin