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

Abstract

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.

Design, synthesis and characterisation of new chimeric ruthenium(ii)–gold(i) complexes as improved cytotoxic agents

“…Bimetallic or trimetallic molecules such as titanocenes incorporating Ru(II), Pt(II) and Pd(II) centers, 18,19 and a number of derivatives containing ferrocene moieties and other metals 20 were recently described. Heterometallic compounds incorporating gold(I) fragments have been reported for titanocene, 19,21,22 ruthenocene, 23 platinum(II) 24 and rhenium(I) derivatives. 25 Ferrocenyl phosphanes were also incorporated in the iminophosphorane skeleton of gold(III) coordination complexes.…”

“…In addition, the incorporation of gold and of a second metal within the same molecule may offer advantages in their use as potential anticancer derivatives. Improved stability, 21–22 solubility 21,22 or lower toxicity in vivo 22 with respect to the individual monometallic fragments, or a beneficial combination of medicinal properties ( e.g. a cell imaging agent plus a cytotoxic agent) 22 were reported.…”

“…Improved stability, 21–22 solubility 21,22 or lower toxicity in vivo 22 with respect to the individual monometallic fragments, or a beneficial combination of medicinal properties ( e.g. a cell imaging agent plus a cytotoxic agent) 22 were reported. Nevertheless, studies on the possible mechanism of heterometallic complexes are still scarce 19,20,22 and at a preliminary stage, and there is definitely a real need to understand their interactions with different biological targets to assess the role exerted by each individual metal center.…”

Newly-presented potential targeted drugs in the treatment of renal cell cancer

“…Their results reveal that YM155 is a potentially novel strategy reverse the resistance in RCC. [41] evaluated the potential anticancer activity of the compounds. They found that the organometallic 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, suggesting a synergistic function of the resulting heterometallic species.…”

Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors

“…2 Several new lines of research suggest that gold(I) has a significant potential as a component of therapies designed to inhibit therapeutically relevant targets, such as zinc-finger domains 3 and protein kinases. 4 …”