Synthesis, characterisation and antiviral activity of platinum(II) complexes with 1,10-phenanthrolines and the antiviral agents acyclovir and penciclovir

Four novel hybrid drugs [Pt(acy)(2)(Me(2)phen)]I-2 (1), [Pt(pen)(2)-(Me(2)phen)](No-3)(2) (2), [Pt(acy)(2)(phen)](NO3)(2) (3), and [Pt(pen)(2)(phen)](NO3)(2) (4) have been prepared by reaction of the antiviral guanine derivatives acyclovir (acy) and penciclovir (pen) with platinum complexes having 2,9-Me-2-1,10-phenanthroline (Me2phen) and l,10-phenanthroline (phen) as carrier ligands. Both the Me(2)phen and phen carrier ligands are able to hinder rotation of the guanine bases about the Pt-N(7) bonds rendering the interconversion among rotamers very slow on the NMR time scale. A favourable dipole-dipole interaction between the cis-coordinated purine bases stabilises the HT rotamers, which are the only species detected in solution. The stability in a physiological medium and the anti-HIV properties in vitro of the complexes have been evaluated. In a 0.1 M solution of NaCl, the compounds with Me(2)phen (1 and 2) were found to be very stable while the compounds with phen (3 and 4) underwent displacement of one purine base by a chloride ion. This rather unexpected result may have some relevance in connection with the stability of major DNA adducts of cisplatin in which two guanines are cross-linked by a Pt(NH3)(2) moiety. Although none of the complexes showed anti-HIV activity complexes 1 and 2, bearing methyl substituents in the ortho positions of the phenanthroline, were much more cytotoxic than 3 and 4. This is probably due to a greater stability of the former complexes in biological media caused by the presence of the two methyl groups wrapping the metal centre and inhibiting the nucleophilic attack of an incoming ligand at the platinum centre.