Early-late transition
metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential
anticancer agents in vitro against renal and
prostate cancer cell lines. The compounds were significantly more effective than monometallic
titanocene dichloride and
gold(I) [{HOC(O)RPPh2}AuCl] (R = -CH2- 6, -4-C6H4- 7) derivatives in
renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on
renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of
cisplatin and highly active
titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro 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 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro 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 5) are excellent candidates for further development as potential
renal cancer chemotherapeutics.