Importance of Platinum(II)-Assisted Platinum(IV) Substitution for the Oxidation of Guanosine Derivatives by Platinum(IV) Complexes

Guanosine derivatives with a nucleophilic group at the 5′ position (G-5′) are oxidized by the PtIV complex Pt(d,l)(1,2-(NH2)2C6H10)Cl4 ([PtIV(dach)Cl4]). The overall redox reaction is autocatalytic, consisting of the PtII-catalyzed PtIV substitution and two-electron transfer between PtIV and the bound G-5′. In this paper, we extend the study to improve understanding of the redox reaction, particularly the substitution step. The [PtII(NH3)2(CBDCA-O,O′)] (CBDCA = cyclobutane-1,1-dicarboxylate) complex effectively accelerates the reactions of [PtIV(dach)Cl4] with 5′-dGMP and with cGMP, indicating that the PtII complex does not need to be a PtIV analogue to accelerate the substitution. Liquid chromatography/mass spectroscopy (LC/MS) analysis showed that the [PtIV(dach)Cl4]/[PtII(NH3)2(CBDCA-O,O′)]/cGMP reaction mixture contained two PtIVcGMP adducts, [PtIV(NH3)2(cGMP)(Cl)(CBDCA-O,O′)] and [PtIV(dach)(cGMP)Cl3]. The LC/MS studies also indicated that the trans,cis-[PtIV(dach)(37Cl)2(35Cl)2]/[PtII(en)(35Cl)2]/9-EtG mixture contained two PtIV-9-EtG adducts, [PtIV(en)(9-EtG)(37Cl)(35Cl)2] and [PtIV(dach)(9-EtG)(37Cl)(35Cl)2]. These PtIVG products are predicted by the Basolo−Pearson (BP) PtII-catalyzed PtIV-substitution scheme. The substitution can be envisioned as an oxidative addition reaction of the planar PtII complex where the entering ligand G and the chloro ligand from the axial position of the PtIV complex are added to PtII in the axial positions. From the point of view of reactant PtIV, an axial chloro ligand is thought to be substituted by the entering ligand G. The PtIV complexes without halo axial ligands such as trans,cis-[Pt(en)(OH)2Cl2], trans,cis-[Pt(en)(OCOCF3)2Cl2], and cis,trans,cis-[Pt(NH3)(C6H11NH2)(OCOCH3)2Cl2] ([PtIV(a,cha)(OCOCH3)2Cl2], satraplatin) did not react with 5′-dGMP. The bromo complex, [PtIV(en)Br4], showed a significantly faster substitution rate than the chloro complexes, [PtIV(en)Cl4] and [PtIV(dach)Cl4]. The results indicate that the axial halo ligands are essential for substitution and the PtIV complexes with larger axial halo ligands have faster rates. When the PtIV complexes with different carrier ligands were compared, the substitution rates increased in the order [PtIV(dach)Cl4] < [PtIV(en)Cl4] < [PtIV(NH3)2Cl4], which is in reverse order to the carrier ligand size. These axial and carrier ligand effects on the substitution rates are consistent with the BP mechanism. Larger axial halo ligands can form a better bridging liga