Synthesis, Characterisation and Antiviral Activity of Platinum(II) Complexes with 1,10-Phenanthrolines and the Antiviral Agents Acyclovir and Penciclovir

Abstract

Four novel hybrid drugs [Pt(acy)2(Me2phen)]I2 (1), [Pt(pen)2(Me2phen)](NO3)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‐Me2‐1,10‐phenanthroline (Me2phen) and 1,10‐phenanthroline (phen) as carrier ligands. Both the Me2phen 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 Me2phen (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.

Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance

“…Platinum compounds with 1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline (Me 2 phen) have already been investigated for antitumor activity [9][10][11][12]. We anticipate that one of the compounds here reported is more active than cisplatin in vitro, has a different spectrum of activity, and is able to overcome acquired cisplatin resistance.…”

“…We chose the Me 2 phen ligand (instead of phen) for two reasons: the better cytotoxicity of [Pt(Me 2 phen)L 2 ] complexes (L = acyclovir or penciclovir) as compared to analogous compounds with phen [9,10] and the role of the ortho-methyl substituents which appear to destabilize the cis iodide, thus favoring its substitution, while not inhibiting coordination of a purine [13,[18][19][20]. In order to look closer to the interligand relationships we performed also an X-ray investigation of compound 2 which was obtained as nice-shaped pale-yellow crystals.…”

Antiviral properties and cytotoxic activity of platinum(II) complexes with 1,10-phenanthrolines and acyclovir or penciclovir

“…The synthesis of hybrid drugs combining in the same molecule the features of cis-amine platinum antitumor compounds and the antiviral properties of guanine analogues has attracted our attention in recent years [1][2][3][4][5][6]. These compounds contain, in the same molecule, a cisplatin-like moiety (a potent anticancer drug, known to bind to cellular DNA after activation via intracellular aquation) [7][8][9][10] and acyclovir (a synthetic derivative of guanosine having a linear chain in place of the ribose sugar in position 9 of the purine residue and found to be the first highly active antiviral drug; acy in Scheme 1) [11,12].…”

“…Four novel hybrid complexes having as platinum carrier ligands the aromatic diimines 1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline (phen and Me 2 phen, respectively) and the antiviral guanosine derivatives acyclovir and penciclovir (acy and pen, respectively; Scheme 1) coordinated to the metal through N(7), were synthesised [5].…”

“…A different case is that of the cisplatin analogue ZD0473 [cis-amminedichloro(2-methylpyridine)platinum(II)], in which, being the steric bulk created outside the plane of coordination, the rate of substitution of the leaving chlorides by an incoming nucleophile is most affected [18][19][20]. Preliminary data [5] showed that some of the complexes had significant cytotoxic activity therefore we decided to further extend this investigation. In this paper, we report on the antiviral properties, the in vitro cytotoxicity, and the in vivo antitumoral activity of the derivatives [Pt(Me 2 phen)-(acy) 2 ] 2þ (1), [Pt(Me 2 phen)(pen) 2 ] 2þ (2), [Pt(phen)(acy) 2 ] 2þ (3), and [Pt(phen)(pen) 2 ] 2þ (4) (Scheme 2).…”