Reactivity of Ammonia Ligands of the Antitumor Agent Cisplatin: A Unique Dodecanuclear Pt4,Pd4,Ag4 Platform for Four Cytosine Model Nucleobases

• Published in: Chemistry : a European journal Vol. 14; no. 23; pp. 6882 - 6891
• Main Authors: Kampf, Gunnar, Sanz Miguel, Pablo J., Morell Cerdà, Marta, Willermann, Michael, Schneider, Alexandra, Lippert, Bernhard
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 08.08.2008; WILEY‐VCH Verlag
• Subjects: Ammonia - chemistry; Antineoplastic Agents - chemistry; bioinorganic chemistry; bridging ligands; Cisplatin - chemistry; Crystallography, X-Ray; Cytosine - chemistry; heterometallic complexes; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; nucleobases; Palladium - chemistry; platinum; Platinum - chemistry; Pyridines - chemistry; Silver - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200800586

The reaction of a potential mono(nucleobase) model adduct of cisplatin, cis‐[Pt(NH3)2(1‐MeC‐N3)(H2O)]2+ (6; 1‐MeC: 1‐methylcytosine), with the electrophile [Pd(en)(H2O)2]2+ (en: ethylenediamine) at pH≈6 yields a kinetic product X which is likely to be a dinuclear Pt,Pd complex containing 1‐MeC−‐N3,N4 and OH bridges, namely cis‐[Pt(NH3)2(1‐MeC−‐N3,N4)(OH)Pd(en)]2+. Upon addition of excess Ag+ ions, conversion takes place to form a thermodynamic product, which, according to 1H NMR spectroscopy and X‐ray crystallography, is dominated by a μ‐NH2 bridge between the PtII and PdII centers. X‐ray crystallography reveals that the compound crystallizes out of solution as a dodecanuclear complex containing four PtII, four PdII, and four Ag+ entities: [{Pt2(1‐MeC−‐N3,N4)2(NH3)2(NH2)2(OH)Pd2(en)2Ag}2{Ag(H2O)}2](NO3)10⋅ 6 H2O (10) is composed of a roughly planar array of the 12 metal ions, in which the metal ions are interconnected by μ‐NH2 groups (between Pt and Pd centers), μ‐OH groups (between pairs of Pt atoms), and metal–metal donor bonds (Pt→Ag, Pd→Ag). The four 1‐methylcytosinato ligands, which are stacked pairwise, as well as the four NH3 ligands and parts of the en rings, are approximately perpendicular to the metal plane. Two of the four Ag ions (Ag2, Ag2′) of 10 are labile in solution and show the expected behavior of Ag+ ions in water, that is, they are readily precipitated as AgCl by Cl− ions. The resulting pentanuclear complex [Pt2Pd2Ag(1‐MeC−)2(NH2)2(OH)(NH3)2(en)2](NO3)4⋅7 H2O (11) largely maintains the structural features of one half of 10. The other two Ag+ ions (Ag1, Ag1′) of 10 are remarkably unreactive toward excess NaCl. In fact, the pentanuclear complex [Pt2Pd2AgCl(1‐MeC−)2(NH2)2(OH)(NH3)2(en)2](NO3)3⋅4.5 H2O (12), obtained from 10 with excess NaCl, displays a Cl− anion bound to the Ag center (2.459(3) Å) and is thus a rare case of a crystallized “AgCl molecule”. Cisplatin ligands are anything but inert! A simple monoadduct of cisplatin with a cytosine nucleobase condenses, in the presence of (ethylenediamine)PdII species and Ag+ ions, to form heteronuclear Pt2,Pd2,Ag and Pt4,Pd4,Ag4 species displaying μ‐NH2 and μ‐OH bridges (see structure), stacked nucleobases, and metal→metal donor bonds, as well as a surprising unreactivity of the Ag+ ion in the Pt2,Pd2,Ag species toward Cl− ions.