On the Heterogeneous Nature of Cisplatin‐1‐Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH₃ Ligands as Likely Explanation

Abstract

The conversion of the 1 : 1-complex of Cisplatin with 1-methyluracil (1MeUH), cis-[Pt(NH 3) 2 (1MeU-N3)Cl] (1 a) to the aqua species cis-[Pt(NH 3) 2 (1MeU-N3)(OH 2)] + (1 b), achieved by reaction of 1 a with AgNO 3 in water, affords a mixture of compounds, the composition of which strongly depends on sample history. The complexity stems from variations in condensation patterns and partial loss of NH 3 ligands. In dilute aqueous solution, 1 a, and dinuclear compounds cis-[(NH 3) 2 (1MeU-N3)Pt(μ-OH)Pt(1MeU-N3)(NH 3) 2 ] + (3) as well as head-tail cis-[Pt 2 (NH 3) 4 (μ-1MeU-N3,O4) 2 ] 2 + (4) represent the major components. In addition, there are numerous other species present in minor quantities, which differ in metal nuclearity, stoichiometry, stereoisomerism, and Pt oxidation state, as revealed by a combination of 1 H NMR and ESI-MS spectroscopy. Their composition appears not to be the consequence of a unique and repeating coordination pattern of the 1MeU ligand in oligomers but rather the coexistence of distinctly different condensation patterns, which include μ-OH, μ-1MeU, and μ-NH 2 bridging and combinations thereof. Consequently, the products obtained should, in total, be defined as a heterogeneous mixture rather than a mixture of oligomers of different sizes. In addition, a N 2 complex, [Pt(NH 3)(1MeU)(N 2)] + appears to be formed in gas phase during the ESI-MS experiment. In the presence of Na + ions, multimers n of 1 a with n = 2, 3, 4 are formed that represent analogues of non-metalated uracil quartets found in tetrastranded RNA.

Beyond Sole Models for the First Steps of Pt-Dna Interactions: Fundamental Properties of Mono(Nucleobase) Adducts of Ptii Coordination Compounds

“…by iodide, we have later demonstrated that it is possible to convert cis-[Pt (NH 3 ) 2 (nb)X] compounds in reasonable yields readily into trans-[Pt(NH 3 )(nb)X 2 ] [163]. Examples with nb being purine bases have likewise been obtained this way [197], as have been two species containing the pyrimidine base 1MeU [49,73].…”

“…Yields of the 1:1-complexes are frequently moderate or low due to concomitant formation of the corresponding bis (nucleobase) complex, and the possibility of subsequent secondary reactions of either species with the remaining available Pt starting compound [48]. Occasionally, detour reactions to obtain the desired mono(nucleobase) species can be advantageous [49]. Binding sites of the model nucleobase to Pt II usually follow expectations [50], as outlined above.…”

“…6). They might explain, at least in part, the complexity of 1 H NMR spectra of freshly prepared cis-[Pt [48,49]. The use of unsymmetrical rather than symmetrical co-ligands ((NH 3 ) 2 , en, 2,2 0 -bpy, etc.)…”

“…These findings tentatively suggest that the Ag + ions might also be substituted by other hetero metal ions, including by cis-Pt II (-NH 3 ) 2 units, thereby generating oligomeric species, with the possibility to undergo partial oxidation. In fact, ''platinum blues" are also formed from head-tail dinuclear complexes of 1MeU, the composition and ways of formation of which remains unclear, however [49].…”

“…An obvious crucial question remains: What happens, when cyclization of di-or trinuclear entities or even larger ones does not occur, or when cyclic species open, either by cleavage of a Pt-X4 bond (in pym complexes) or possibly even a Pt-N3 bond (1MeC -H )? Mass spectra carried out to answer the question regarding the composition of species larger than dimers or trimers are inconclusive considering the multitude of feasible structures [49,163]. Even if assuming that the nucleobase donor atoms remain as seen in the cyclic species within a linear oligomer, namely preferentially through N3 and X4 for the pym bases, the number of feasible open chain structures is large.…”