STUDIES OF PLATINUM(II) METHIONINE COMPLEXES - METABOLITES OF CISPLATIN

Reactions of L-methionine (L-MetH) with [PtX4]2- (X = Cl, Br, I) in 1:1 and 2:1 mole ratios have been studied in aqueous solutions at pHs from 1.9 to 8.7 using H-1, C-13, N-15, and Pt-195 NMR spectroscopy. Some related reactions of L-ethionine, and D-methionine methyl ester were also studied. For [Pt(L-MetH-S,N)Cl2], two diastereomers were characterized, one present in ca. 10% excess, the major form having an approximate envelope ring conformation and the minor form being a flattened boat, whereas in the crystalline state both isomers have the same ring conformation. The carboxylate group of the diastereomers (pK(a) 2.57) does not coordinate under these conditions. The value of DELTA-G* (74.6 kJ mol-1, 337 K) for S inversion is higher than that for nonchelated analogues. At low pH (ca. 2), the predominant form of the 2:1 complex is the partially-ring-opened species cis-[Pt(L-MetH-S,N)(L-MetH2-S)Cl]2+. This transforms reversibly into ring-closed forms at neutral pH, and of these cis-[Pt(L-Met-S,N)2] predominates by about 10:1 over trans-[Pt(L-Met-S,N)2]. For both of these ring-closed species, the three possible diastereomers (R,R: R,S/S,R; S,S) are resolved in Pt-195 NMR spectra. The 2:1 complexes are thought to be metabolites of the anticancer drug cisplatin. Reactions of cisplatin, cis-[PtCl2(NH3)2], and cis-[Pt(NH3)2(H2O)2]2+ with L-methionine in 1:1 and 1:2 mole ratios, at pH 2-7, were also studied. The assignments of N-15 and Pt-195 resonances were greatly aided by the use of various combinations of natural abundance N-14 and N-15 enrichment in both ammonia and methionine. For 1:1 reactions with cisplatin, the major products are [Pt(L-Met-S,N)(NH3)2]+, cis- and trans-[Pt(L-Met-S,N)(NH3)Cl], and the three diastereomers of cis-[Pt(L-Met-S,N)2], and for the 1:2 reactions the products are the diastereomers R,R-, R,S/S,R-, S,S-cis-[Pt(L-Met-S,N)2], together with minor amounts of R,R-, R,S/S,R-, S,S-trans-[Pt(L-Met-S,N)2].