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
