Guanine-06 methylation reduces the reactivity of d(GpG) towards platinum complexes.
6-methylated guanine dinucleotides were used to study the influence of hydrogen bonding on the specific binding of the antitumor drug cDDP, cis-PtCl2(NH3)2, to DNA. In this interaction, the guanine-06 site appears to be important in explaining the preference for a pGpG-N7(1),N7(2) chelate, which results from H-bridge formation with the ammine ligand of cDDP. Guanine-06 methylated dinucleotides and the nonmodified dinucleotides were reacted with [Pt(dien)Cl]+, cis-PtCl2(NH3)2, and cis-[Pt(NH3)2(H2O)2]2+ and the reaction products were characterized by 1H NMR using pH titrations. Methylation at guanine-06 clearly reduces the preference for the guanine. In competition experiments monitored by NMR and experiments using UV spectrophotometry a decreasing reactivity towards [Pt(dien)(H2O)]2+ and cis-[Pt(NH3)2(H2O)2]2+ was found, in the order of d(GpG) greater than d(GomepG) greater than d(GpGome) greater than d(GomepGome). The difference in reactivity between 5' guanine methylation and 3' guanine methylation is ascribed to differences in the H-bond formation with the backbone phosphate. The resulting reduced stacking of the bases in both modified dinucleotides, compared to the bases in d(GpG), results in a preference for the 3' guanine over 5'.
Struik
A F
AF
Department of Chemistry, Gorlaeus Laboratories, Leiden University, The Netherlands.
Zuiderwijk
C T
CT
van Boom
J H
JH
Elding
L I
LI
Reedijk
J
J
D001667:Binding, Competitive; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D009690:Nucleic Acid Conformation; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship
D003848:Deoxyguanine Nucleotides; D010984:Platinum; D006147:Guanine; D004247:DNA; D002945:Cisplatin