Titanocene–gold complexes containing N-heterocyclic carbene ligands inhibit growth of prostate, renal, and colon cancers in vitro

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

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba ¼ S–C6H4–COO) bound to gold(I)-phosphane fragments through a thiolate group [(h-C5H5)2TiMe(m-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(h-C5H5)2TiMe(m-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(h-C5H5)2Ti {OC(O)-4-C6H4-P(Ph2)AuCl}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds

Study of the reactivity of carbosilane metallodendrimers containing n-donor monodentate or n,n-chelating ruthenium (ii) arene complexes with differents biomolecules

Медицинская биофизик

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

Early–late transition metal TiAu₂ compounds [(η-C₅H₅)₂Ti­{OC­(O)­CH₂PPh₂AuCl}₂] (<b>3</b>) and new [(η-C₅H₅)₂Ti­{OC­(O)-4-C₆H₄­PPh₂AuCl}₂] (<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)­RPPh₂}­AuCl] (R = −CH₂– <b>6</b>, −4-C₆H₄– <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 (IC₅₀ <b>3</b> = 91 nM, IC₅₀ <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

Study of the reactivity of carbosilane metallodendrimers containing n-donor monodentate or n,n-chelating ruthenium (ii) arene complexes with differents biomolecules

Медицинская биофизик

In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer

A series of organometallic ruthenium­(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70–100 mg/mL). Most compounds (especially highly water-soluble <b>2</b>) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of <b>2</b> on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo