[Ag(L)NO(3)] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules

[Image: see text] Complexes [Ag(H2BzPh)NO(3)] (1), [Ag(H2BzpCH(3)Ph)NO(3)] (2), [Ag(H2BzpClPh)NO(3)] (3), and [Ag(H2BzpNO(2)Ph)NO(3)] (4) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its para-methyl-benzoylhydrazone (H2BzpCH(3)Ph), para-chloro-benzoylhydrazone (H2BzpClPh), and para-nitro-benzoylhydrazone (H2BzpNO(2)Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (1–3) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC(50 non-malignant cells)/IC(50 tumor cells)) of complex (1), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (1–3) with DNA suggested that although (1–3) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver(I) to DNA probably does not occur. Complexes (1–3) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin.