Ruolo dei leganti ancillari nella coordinazione delle nucleobasi modello del DNA a complessi fosfinici di Platino(II)

Cisplatin, cis-diamminedichloroplatinum(II), plays an important role as a drug against different tumours (testicle, ovary, bladder and neck). The biological properties of this drug, casually discovered by Rosemberg in 1965, have incited studies on the interactions between Platinum (and other metals) complexes and DNA components (nucleobases, nucleotides and nucleosides). In this thesis is reported a deep study of the coordination of the model nucleobases with Platinum(II) complexes, stabilized by phosphine ligands, analogues to cisplatin. The use of phosphine ligands (L) PMe3, PMe2Ph, PMePh2 and PPh3, characterized by a progressive basicity reduction and steric hindrance increase, led to peculiar and original aspects of the coordination chemistry of the nucleobases concerning the metallation sites and the nuclearity of the isolated compounds. The study is based on the reactivity of neutral complexes cis-L2Pt(ONO2)2 and cationic ones cis-[L2Pt(m-OH)]22+ versus 1-MeCy, 1-MeTy, 9-MeAd and 9-MeGu. Hydroxo complexes cis-[L2Pt(m-OH)]22+ can depronate the NH2 exocyclic group of the 1-MeCy and 9-MeAd to form polynuclear adducts such as cis-[L2Pt{Nucleobase(-H)}]nn+, whose nuclearity depends on the nature of L. Low steric hindrance phosphines form very stable trinuclear species (with dinuclear intermediates species with L = PMe3). In these compounds, the 1-MeCy nucleobase is coordinated through the exocyclic deprotonated nitrogen N4 and the endocyclic nitrogen N3, forming species such as cis-[L2Pt{1-MeCy(-H),N3N4}]nn+ (n = 2, 3). With the PMe2Ph ligand we have been able to characterize a trinuclear asymmetric intermediate, a coordination isomer of the analogue trinuclear symmetric one more termodinamically stable. With PPh3, characterized by a high steric hindrance, a mononuclear species, cis-[L2Pt{1-MeCy(-H)}(1-MeCy)]+ has been obtained where the two nucleobases are coordinated to the same metallic centre with different sites, N3 the neutral cytosine and N4 the deprotonated one. With the 9-MeAd, the phosphine complexes showed a similar reactivity. PMe3 stabilizes a dinuclear specie cis-[L2Pt{9-MeAd(-H),N1N6}]22+ with the nucleobase, bridging two metal centres through the deprotonated exocyclic nitrogen N6 and the exocyclic nitrogen N1. PMe2Ph and PMePh2 stabilize the analogues trinuclear species, where the nucleobases maintain the same coordination mode. PPh3 leads to a change in the coordination mode of the nucleobase and forms a mononuclear specie, where 9-MeAd chelates a Platinum(II) centre through N6 and N7. In the condensation reactions conducted in acetonitrile, less basic phosphines with a high steric hindrance stabilize a new class of acetamidine compounds, where a solvent molecule of CH3CN is inserted into a Pt-Nucleobase bond. The neutral specie cis-L2Pt{1-MeTy(-H)}(ONO2) (L = PPh3) with the deprotonated nucleobase 1-MeTy allows to characterize the mixed complex cis-[L2Pt{1-MeTy(-H)}(1-MeCy,N4)]+ , where the neutral nucleobase 1-MeCy is coordinated through the exocyclic nitrogen N4 with a shift of a proton from N4 to N3. This complex stabilizes the rare imino-oxo tautomer of the 1-MeCy. Complexes cis-L2Pt(ONO2)2 react with the nucleobases 1-MeCty and 9-MeGu in their neutral form, leading to the isolation of mono and bis-adducts X-Ray structurally characterized. Also in this case, the biggest PPh3 phosphine plays an important role in the stabilization of monoadducts. In fact, the X-Ray analysis of these complexes shows a strong p-p interaction between the phenyl rings of the PPh3 and the aromatic rings of the two nucleobases. The substitution of both the nitrato groups leads to the bisadducts analogues cis-[L2Pt(Nucleobase)2]2+, where the nucleobases are coordinated in a head-to-tail fashion. The study of biological activity of the complexes has been focused on four cell lines. So far, only the precursors have been investigated and the results are quite modest in comparison to cisplatin.