Multinuclear cytotoxic metallodrugs: physicochemical characterization and biological properties of novel heteronuclear gold-titanium complexes.

An unprecedented series of titanocene-gold bi- and trimetallic complexes of the general formula [[(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)](m)AuCl(x)](q+) (n = 0, 2, or 4; m = 1, x = 1, q = 0 or m = 2, x = 0, q = 1) have been prepared and characterized spectroscopically. The luminescence spectroscopy and photophysics of one of the compounds, [[(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)PPh(2))TiCl(2)](2)Au]PF(6), have been investigated in 2MeTHF solution and in the solid state at 77 and 298 K. Evidence for interfragment interactions based on the comparison of electronic band positions and emission lifetimes, namely, triplet energy transfer (ET) from the Au- to the Ti-containing chromophores, is provided. The cytotoxicity of the complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR; the compounds showed activity in the low micromolar range that was markedly more active than the corresponding titanocene-phosphine precursors [(η(5)-C(5)H(5))(η(5)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)], cisplatin, and, for some of them, the gold analogue [(PPh(3))AuCl]. In an attempt to draw preliminary structure-activity relationships, cell uptake measurements and interaction studies with plasmid DNA and the model protein ubiquitin (Ub) have been undertaken on some of the compounds.