Substitution and Reduction of Platinum(IV) Complexes by a Nucleotide, Guanosine 5‘-Monophosphate

Abstract

A series of Pt(IV) anticancer complexes with different reduction potentials has been investigated for their reactivity toward 5'-guanosine monophosphate (5'-GMP). The Pt(IV) complexes studied were Pt(IV)(trans-d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4) (tetraplatin, Pt(IV)(dach)Cl(4); dach = diaminocyclohexane), cis,trans,cis-[Pt(IV)((CH(3))(2)CHNH(2))(2)(OH)(2)Cl(2)] (iproplatin, Pt(IV)(ipa)(2)(OH)(2)Cl(2); ipa = isopropylamine), cis,trans,cis-[Pt(IV)(en)(OH)(2)Cl(2)] (Pt(IV)(en)(OH)(2)Cl(2); en = ethylenediamine), Pt(IV)(en)Cl(4), and cis,trans,cis-[Pt(IV)(en)(OCOCH(3))(2)Cl(2)] (Pt(IV)(en)(OCOCH(3))(2)Cl(2)). The reactivity was monitored by the decreased (1)H NMR peak intensity at 8.2 ppm due to H8 of free 5'-GMP and the increased intensity of a new peak around 8.6 ppm due to H8 of 5'-GMP bound to Pt(II). The reactivity followed the order of cathodic reduction potentials of the Pt(IV) complexes: Pt(IV)(dach)Cl(4) (-90 mV) >> Pt(IV)(en)Cl(4) (-160 mV) > Pt(IV)(en)(OCOCH(3))(2)Cl(2) (-546 mV) > Pt(IV)(ipa)(2)(OH)(2)Cl(2) (-730 mV). The most reactive complex, Pt(IV)(dach)Cl(4), showed an additional weak peak at 9.2 ppm due to H8 of the 5'-GMP bound to the Pt(IV) complex, indicating the existence of a Pt(IV) intermediate. (1)H NMR, UV/visible absorption spectra, and high-performance liquid chromatograms suggest that the final product is Pt(II)(dach)(5'-GMP)(ox5'-GMP), where ox5'-GMP is oxidized 5'-GMP. A plausible mechanism is that there is an initial substitution of one Pt(IV)/ligand by a 5'-GMP molecule, followed by a two-electron reduction, and finally a second substitution by another 5'-GMP. In the presence of excess 5'-GMP (at least 20-fold), ox5'-GMP seems to be replaced by 5'-GMP to form Pt(II)(dach)(5'-GMP)(2). UV/visible absorption spectroscopy shows that the formation of the Pt(IV) intermediate by substitution is a very slow process followed by reduction. The reduction is characterized by a relatively fast exponential decay. The addition of a small amount of cis-[Pt(II)(NH(3))(2)Cl(2)] shortened the slow formation time of the intermediate, implicating the occurrence of a Pt(II)-assisted substitution reaction. These reactions may lead to a better understanding of the anticancer activity of Pt(IV) complexes.

UV-Vis, HPLC, and 1H-NMR studies of the substitution reactions of some Pt(IV) complexes with 5′-GMP and L-histidine

“…Reduction could be catalyzed in the presence of Pt(II), however, Pt(II) does not need to be an analog to Pt(IV) to accelerate the substitution [17]. Using different methods of analysis confirmed that two electrons needed for the reduction come from the sugar portion of 5 0 -GMP [16][17][18][19].…”

“…Published results for the substitution of different Pt(IV) complexes show that their reactivity depends on their reduction potential [13,16]. For diammine complexes of platinum, the structure variation of diammine ligand has less effect on the rate of reduction, but the nature of axial ligands has higher influence on reduction potential [13,17].…”

“…Reactivity of Pt(IV) complexes toward nucleotide guanosine-5 0 -monophosphate (5 0 -GMP) is frequently studied [16][17][18][19][20]. Nucleotide is coordinated to Pt(IV) via N7 of purine base as for Pt(II) complexes.…”

Protonated nucleobase ligands: synthesis, structure and characterization of 9-methyladeninium hexachloroplatinate and pentachloro(9-methyladeninium)platinum(IV)

“…Ligand substitution reactions using [PtCl 4 (dach)] (dach ¼ cisand trans-1,2-diaminocyclohexane) failed or resulted in platinum(II) complexes [28,29]. In some cases intermediate platinum(IV) complexes could be detected [7,30]. A spontaneous reduction of a 9-methylguanine platinum(IV) complex is reported when dissolved in water [21].…”

“…A spontaneous reduction of a 9-methylguanine platinum(IV) complex is reported when dissolved in water [21]. Furthermore, it was found that Pt(II) may accelerate ligand substitution reactions of Pt(IV) complexes [4,[29][30][31].…”