Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

Early–late transition metal TiAu<sub>2</sub> compounds [(η-C<sub>5</sub>H<sub>5</sub>)<sub>2</sub>Ti­{OC­(O)­CH<sub>2</sub>PPh<sub>2</sub>AuCl}<sub>2</sub>] (<b>3</b>) and new [(η-C<sub>5</sub>H<sub>5</sub>)<sub>2</sub>Ti­{OC­(O)-4-C<sub>6</sub>H<sub>4</sub>­PPh<sub>2</sub>AuCl}<sub>2</sub>] (<b>5</b>) were evaluated as potential anticancer agents <i>in vitro</i> against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold­(I) [{HOC­(O)­RPPh<sub>2</sub>}­AuCl] (R = −CH<sub>2</sub>– <b>6</b>, −4-C<sub>6</sub>H<sub>4</sub>– <b>7</b>) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for <b>5</b> in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells <i>in vitro</i> coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC<sub>50</sub> <b>3</b> = 91 nM, IC<sub>50</sub> <b>5</b> = 117 nM). The selectivity of the compounds <i>in vitro</i> against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially <b>5</b>) are excellent candidates for further development as potential renal cancer chemotherapeutics.