Platinum, complexed with methionine

Gurnmin, D. D., Ratilla, E. M. A. and Kostic, N. M. (1986) Variable-temperature platinum-195 NMR spectroscopy, a new technique for the study of stereodynamics, sulfur inversion in a platinum(II) complex with methionine. Inorg. Chem., 25, 2429-2433. 

A general role for a thiol reaction with platinum complexes as deactivation cannot at present be stated, although tissue binding involving sulfhydryl groups is well documented and biochemical aspects have been discussed (Chapter 2.4). The reactions of Pt complexes with methionine... 

The platinum(II) catalyzed reduction of civ,civ,/rart.v-diaminedihalodihydroxoplatinum(IV) complexes by ascorbate has been reported to proceed via a long-lived platinum(IV)-ascorbate radical.518 Ascorbate reduction of complexes with halides in the axial sites has been reported to proceed via reductive attack on one of these halides.519 This group also showed that reduction by A sc2 occurred seven orders of magnitude more rapidly than reduction by I IAsc and that H2Asc is unreactive.519 Reduction by thiols and methionine is strongly dependent on pH because of a similar variation in reactivity of the protonated and unprotonated forms of the reductants.505,514... 

Platinum compounds have been widely used. These include the PtCl ion or the less reactive cis or trans platinum diaminodichloride compounds. At acid pH they react with methionine, cystine disulphides, N-termini or histidine. In the presence of ammonium sulphate, the chloride ions are rapidly substituted by ammonium ions to form [Pt(NH3)4] which is unreactive. Square planar negatively charged complexes such as Pt(CN)4 have been found to be effective in binding at the nucleotide-binding site in dehydrogenases. The cyanide ligands are firmly bound to the metal and are not displaced by protein atoms. 

The reactions of cw-[Pt(NH3)2Cl(OH2)] with L-methionine under an acidic condition and at pH ss 7 have been investigated by ID Pt and N NMR as well as 2D [ H, Nj HSQC NMR [74]. When the platinum complex is in excess in an acidic solution, the initial product, cw-[Pt(NH3)2Cl(Met-S)]+ undergoes slow ring closure to cw-[Pt(NH3)2(Met-N,S)f+. Slow ammine loss occurs to produce the isomer of c -[Pt(NH3)Cl(Met-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which tra 5 -[Pt(NH3)Cl(Met-S)2]+ isomerizes to the cis isomer, with subsequent ring closure reactions leading to the formation of cw-[Pt(Met-N,S)2] +. In contrast to methionine which is unreactive toward cw-[Pt(NH3)2Cl(OH)] at pH 7,... 

Substitution of aqua ligands by nitrogen donors such as the nucleic acid bases leads to mono- and disubstituted complexes whose properties, of course, have been extensively studied (Chapter 4). Once inside the cell, however, only a small proportion of the platinum is complexed to the DNA. Metabolism of the platinum complexes therefore takes place with other biomolecules besides DNA. Amino acid reactions may take place which may sequester the complex. Further, in the case of substitution by nucleophiles with strong tram influence, especially those of sulfur, displacement of amine and deactivation may occur. Interestingly, amine labilization tram to a thioether in d5-[Pt(NH3)2(Me2S)2] has been observed [107]. In vivo, thioethers such as methionine could effect the same chemistry and the characterization of [Pt(methionine)2], assigned the structure as shown, as a metabolite of cisplatin [108] confirms this view ... 

The anticancer activity of platinum(IV) complexes, and the belief that reduction is needed to initiate this activity, had generated substantial interest in the rates and mechanism of reduction by biologically relevant reductants such as thiols, ascorbic acid, and methionine. Reduction of platinum(IV) to platinum(II) usually proceeds as a single two-electron step and is usually first-order with respect to both platinum(IV) and reductant concentrations. 

In cytochrome-c [PtCU]2- binds to methionine 65 on the outside of the protein (64). Again the chloride is probably displaced as the reagent is applied in phosphate buffer. Dickerson and co-workers consider that the platinum is oxidized to a Pt(IV) complex but this seems unlikely as it does not occur in the reaction of [PtClJ2- with simple amino-acids. 

Displacement of Pt-S-Bound L-Methionine by 5 -GMP. In an effort to understand why cisplatin reacts with 5 -GMP even in the presence of methionine, Barnham et al. [83] performed a competitive reaction experiment between [Pt(dien)Cl]Cl, L-methionine, and 5 -GMP. They observed that, in the first 40 hours of the reaction, the methionine was platinated to yield [Pt(dien)(Met-S )]2+, whereas only little of the 5 -GMP had reacted. In the latter stages of the reaction, this complex disappears as the platinum binds to 5 -GMP, resulting in the complex [Pt(dien)(5 -GMP, N(7))]2+ and free methionine. The kinetics of the displacement reaction were studied and the half-life of the reaction was determined to be 167 h at 310 K. The calculated 77 and. S values for this displacement reaction are indicative of a sub-... 

Reactions between the sulfur-containing amino acids cysteine and methionine (Fig. 2.18) and rufhenium(II) arene anticancer complexes are of much interest in view of the strong influence of sulfur amino acids on the intracellular chemistry of platinum drugs, their involvement in detoxification and resistance mechanisms [100]. We found [101] that [(ri -biphenyl)Ru(en)Cl][PF 5] reacts slowly with the thiol amino add L-cysteine in aqueous solution at 310 K, pH 2-5, and only to about 50% completion at a 1 2 mM ratio. Reactions appeared to involve aquation as the first step followed by initial formation of 1 1 adducts via substitution of water by S-bound or O-bound cysteine. Two dinuclear complexes were also detected as products from the reaction. In these reactions half or all of the chelated ethylene-diamine had been displaced and one or two bridging cysteines were present The unusual cluster species (biphenyl) Ru g was also formed espedaUy at higher cysteine concentrations. The reaction was suppressed in 50 mM triethylammo-nium acetate solution at pH > 5 or in 100 mM NaCl suggesting that thiols may not readily inactivate Ru(II)-en arene complexes in blood plasma or in cells. Similarly, reactions with the thioether sulfur of methionine appeared to be relatively weak. Only 27% of [(r -biphenyl)Ru(en)Cl][PF5] reacted with L-methionine (L-MetH) at an initial pH of 5.7 after 48 h at 310 K, and gave rise to only one adduct [(ri -biphenyl) Ru(en) (i-MetH -S)]. ... 

---