Synthesis and stereochemical characterisation of platinum(II) complexes with the antiviral agents penciclovir and famciclovir

Abstract

The synthesis and the stereochemical characterisation of platinum complexes containing one molecule of antiviral drug, penciclovir or famciclovir (L), and different sets of ancillary ligands (Cl x (NH 3) 3− x , x=1 or 2, and N, N, N′, N′′, N′′-pentamethyldiethylenetriamine, pmdien) are reported. Penciclovir is a guanosine analogue, while famciclovir is a prodrug of penciclovir lacking the oxygen in position 6 of the purine ring. The investigation has allowed comparison of structural features of platinum derivatives with different bulk of the carrier ligand(s) and of the purines. NMR experiments (particularly diagnostic are the H8 and H6 chemical shifts of the purine) indicate that in compounds with non-bulky carrier ligands (Cl x (NH 3) 3− x ) the purine is free to rotate about the PtN7 bond. In contrast, in complexes with bulky carrier ligand (pmdien) there is restricted rotation about the PtN7 bond and the purine is constrained in a “quasi orthogonal” position with respect to the platinum coordination plane. Because of the slow rotation for [Pt(pmdien)(L)] 2+ two rotamers are observed in solution differing for the relative positions of the six-membered ring of the purine and the central N-methyl of pmdien with respect to the platinum coordination plane (on the same side or on opposite sides for endo and exo rotamers, respectively). Penciclovir, having an oxygen atom in position 6 of the purine ring, favours the exo over the endo rotamer while famciclovir, having just a hydrogen atom in position 6, favours the endo over the exo rotamer. The change in rotamer preference suggests that intramolecular interactions involving mostly the substituent in position 6 of the purine and the terminal N-methyls of pmdien have opposite character for the two antiviral ligands. Biological tests have confirmed that cationic platinum species of formula cis-[PtCl(NH 3) 2(L)] + can have cytotoxicity towards tumour cells greater than corresponding compounds of formula cis-[PtCl 2(NH 3)(L)].