Titanocene–Gold Complexes Containing N-Heterocyclic Carbene Ligands Inhibit Growth of Prostate, Renal, and Colon Cancers in Vitro

Abstract

We report on the synthesis, characterization, and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = −OC(O)-p-C6H4-S−) bound to gold(I)–N-heterocyclic carbene fragments through the thiolate group: [(η5-C5H5)2TiMe(μ-mba)Au(NHC)]. The cytotoxicities of the heterometallic compounds along with those of novel monometallic gold–N-heterocyclic carbene precursors [(NHC)Au(mbaH)] have been evaluated against renal, prostate, colon, and breast cancer cell lines. The highest activity and selectivity and a synergistic effect of the resulting heterometallic species was found for the prostate and colon cancer cell lines. The colocalization of both titanium and gold metals (1:1 ratio) in PC3 prostate cancer cells was demonstrated for the selected compound 5a, indicating the robustness of the heterometallic compound in vitro. We describe here preliminary mechanistic data involving studies on the interaction of selected mono- and bimetallic compounds with plasmid (pBR322) used as a model nucleic acid and the inhibition of thioredoxin reductase in PC3 prostate cancer cells. The heterometallic compounds, which are highly apoptotic, exhibit strong antimigratory effects on the prostate cancer cell line PC3.

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

“…In the case of PC3 cells treated with 30 μM of monometallic gold compounds ( 73 , 74 ) there was inhibition of TrxR but to a lower extent (30 and 36% for 73 and 74 , respectively, after 24 hr incubation). Particularly, compounds 75 and 76 exhibited selective cytotoxicity to cancer cells (Table ) …”

Heterobimetallic Complexes for Theranostic Applications

“…[7] Additionally,i th as been provent hat the presence of two metallicf ragments exerts ac ooperative effect in the cytotoxic activity and properties of the final complexes.M oreover,t hey are often prone to overcome cellular resistance, because of the possibility of combining the different intrinsic mechanism of action of each metallicf ragment. Examples of this are illustrated in Figure 2, in which normally the coordination sphere of the metalsa lready emulates ak nown bioactive metallic environment,s uch as for instance Ru II as RAPTA, [8] Pt II as cisplatin, [9] Ti IV as titanocene, [10] and Au I as auranofin. [11] Cell Imaging Agents…”

“…With this idea in mind, we pioneered the first bimetallic d 6 -d 10 opticaltrackableprobe designed for such ap urpose, specifical- Figure 5. Designofa noptical theranosticagents.…”

(Benzyl isocyanide)gold(I) pyrimidine‐2‐thiolate complex: Synthesis and biological activity

“…Several complexes based on thiolate ligands especially of the type L−Au(I)−SR have been prepared. In these complexes L is a neutral ligand such as phosphine, N‐heterocyclic carbene or isocyanide . In general, the presence of the various L donor ligands and thiolate ligands in the structure of these complexes leads to a wide range of applications particularly in cancer treatment …”