Mechanism of Two-Electron Oxidation of Deoxyguanosine 5‘-Monophosphate by a Platinum(IV) Complex

• Published in: Journal of the American Chemical Society 2004-01, Vol.126 (2), p.591-598
• Main Authors: Choi, Sunhee, Cooley, Richard B, Hakemian, Amanda S, Larrabee, Yuna C, Bunt, Richard C, Maupas, Stéphane D, Muller, James G, Burrows, Cynthia J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Deoxyguanine Nucleotides - chemistry; Deoxyguanine Nucleotides - metabolism; Fundamental and applied biological sciences. Psychology; Mechanisms. Catalysis. Electron transfer. Models; Molecular biophysics; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Oxidation-Reduction; Physical chemistry in biology; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja038334m

Many transition metal complexes mediate DNA oxidation in the presence of oxidizing radiation, photosensitizers, or oxidants. The final DNA oxidation products vary depending on the nature of metal complexes and the structure of DNA. Here we propose a mechanism of oxidation of a nucleotide, deoxyguanosine 5‘-monophosphate (dGMP) by trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum (trans-Pt(d,l)(1,2-(NH2)2C6H10)Cl4, [PtIVCl4(dach)]; dach = diaminocyclohexane) to produce 7,8-dihydro-8-oxo-2‘-deoxyguanosine 5‘-monophosphate (8-oxo-dGMP) stoichiometrically. The reaction was studied by high-performance liquid chromatography (HPLC), 1H and 31P nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI-MS). The proposed mechanism involves PtIV binding to N7 of dGMP followed by cyclization via nucleophilic attack of a phosphate oxygen at C8 of dGMP. The next step is an inner-sphere, two-electron transfer to produce a cyclic phosphodiester intermediate, 8-hydroxyguanosine cyclic 5‘,8-(hydrogen phosphate). This intermediate slowly converts to 8-oxo-dGMP by reacting with solvent H2O.