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

Abstract

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-(NH(2))(2)C(6)H(10))Cl(4), [Pt(IV)Cl(4)(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), (1)H and (31)P nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI-MS). The proposed mechanism involves Pt(IV) 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 H(2)O.

De Novo Generation of Singlet Oxygen and Ammine Ligands by Photoactivation of a Platinum Anticancer Complex

“…[8] Although it has been reported that several Pt IV -tetrachlorido complexes can directly oxidize guanine, [12] we report here for the first time that the photodecomposition of a Pt IV -diazidodihydroxido complex can oxidize guanine. Complexes containing Pt II and oxidized guanine as 8-OH-G and RedSp were detected (Table 1).…”

“…There are a number of reports of the chemical reduction of Pt IV to Pt II , and it is widely accepted that a concerted twoelectron transfer from, for example, ascorbate, GSH, or guanine, to Pt IV is involved. [12,15] However, the photoreduction of 1 may not follow the above pathway. Pt IV is more likely to gain one electron from each of the two N 3 or two OH ligands and give rise to N 3 C or OHC radicals, respectively.…”

Reduction Process of Tetraplatin in the Presence of Deoxyguanosine Monophosphate (dGMP): A Computational DFT Study

“…[15,16] Nevertheless, clarification of its activation mechanism can help to understand the reduction processes of similar Pt IV complexes. The reduction mechanism of tetraplatin in the presence of deoxyguanosine monophosphate (dGMP) wass uggested by Choi et al [17][18][19][20] and it is shown in Scheme 1. Accordingt oI Ra nd NMR spectroscopy,a nd liquid chromatography (HPLC)/mass spectrometry measurements, an intermediate, where dGMP is bound to Pt through aP t ÀN7(dGMP) interaction, is initially formed in as ubstitution reaction.Asigmoidal shape of the kinetic curves indicates an autocatalytic course of this first reaction.…”

Model platinum nucleobase and nucleoside complexes and antitumor activity: X-ray crystal structure of [PtIV(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-ethylguanine)Cl]NO3·H2O

“…Thus, the L1210/DACH cell line is able to differentiate between DACH-acetate-Pt(IV) and oxaliplatin, and provides compelling evidence that DACH-Pt(IV) and DACH-Pt(II) are not necessarily alike. It is, therefore, possible that the effectiveness of DACH-acetate-Pt(IV) may not be related to its reduction to the DACH-Pt(II) form, and raise the notion that Pt(IV) complexes could interact directly with the biological target [12,24].…”