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

Early-late transition metal TiAu 2 compounds [(η-C 5 H 5 ) 2 Ti{OC(O)CH 2 PPh 2 AuCl} 2 ] ( 3 ) and new [(η-C 5 H 5 ) 2 Ti{OC(O)-4-C 6 H 4 PPh 2 AuCl} 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)RPPh 2 }AuCl] (R = -CH 2 - 6 , -4-C 6 H 4 - 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 (IC 50 3 = 91 nM, IC 50 5 = 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.