Biological Investigations of Ru(II) Complexes with Diverse β‐Diketone Ligands

Abstract

The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different k 2 -O,O'-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a~30fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that k 2 -O,O'-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

Ru(II)-Based Acetylacetonate Complexes Induce Apoptosis Selectively in Cancer Cells

“…36 Similarly, other studies on bpy-based Ru complexes with similar acacbased ligands showed higher toxicity compared to our complexes when tested against cancerous cell lines like HL60, MIA PaCa-2, and DU-145 cells, but no studies regarding selectivity of these complexes toward cancerous vs non-cancerous cell lines have been mentioned by the authors. 39 Reports on cancer cell selectivity have also not been reported with Ru(II) polypyridyl complexes containing acac-based ligand curcumin and Ru(II) polypyridyl complexes containing D-glucose and D-fructose conjugated acac-based ligands. 37,38 Therefore, we can say that complex 1 is currently the only known acac-based Ru polypyridyl complex, which shows selectivity for a cancerous vs normal cell line.…”

“…Ru(II) complexes with the general formula [Ru(bpy) 2 (L)] + , where bpy = 2,2′-bipyridine and L is a diverse array of κ 2 -O-O′ chelating β-diketone ligands including acetylacetonate (acac), showed nanomolar potency against DU-145 cells (human prostate cancer) and MIA PaCa-2 cells (human pancreatic cancer). 39 In vivo toxicity of these complexes was evaluated in a zebrafish model, where data indicated that most complexes were nontoxic in vivo. Curcumin (a type of κ 2 -O-O′ chelating β-diketone ligand)based polypyridyl Ru(II) complexes with formulae [Ru-(bpy) 2 (curcumin)] + and [Ru(bpy)(dppn)(curcumin)] + , where dppn = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine, showed single-digit micromolar potency against A549, MCF-7, and SGC7901 cell lines.…”

“…Ru­(II) polypyridyl complexes with different types of dioxo ligands have shown promise as potential anticancer agents. − Among those Ru­(II) polypyridyl complexes, analogues with acetylacetonate-based ligands have been particularly active. Ru­(II) complexes with the general formula [Ru­(bpy) 2 (L)] + , where bpy = 2,2′-bipyridine and L is a diverse array of κ 2 -O-O′ chelating β-diketone ligands including acetylacetonate (acac), showed nanomolar potency against DU-145 cells (human prostate cancer) and MIA PaCa-2 cells (human pancreatic cancer) …”

Ruthenium(II) Polypyridyl Complexes Containing Simple Dioxo Ligands: a Structure‐Activity Relationship Study Shows the Importance of the Charge

“…In a recent paper, Glazer et al. investigated a series of cationic [Ru(bpy) 2 (O^O)] + complexes, where O^O is acac or a substituted acac [24] . They found that the in vitro cytotoxicity of the complexes roughly correlates with the lipophilicity/hydrophobicity of the acac ligand (and thus of the complex) [24] .…”

“…investigated a series of cationic [Ru(bpy) 2 (O^O)] + complexes, where O^O is acac or a substituted acac [24] . They found that the in vitro cytotoxicity of the complexes roughly correlates with the lipophilicity/hydrophobicity of the acac ligand (and thus of the complex) [24] . The cytotoxic activity of complex 4 is consistent with these results; in Glazer's complexes, the lipophilicity of the substituted‐acac ligands compensates for the less lipophilic bpy ligand (compared to DIP).…”