Bis(bipyridine)ruthenium(II) Ferrocenyl β‐Diketonate Complexes: Exhibiting Nanomolar Potency against Human Cancer Cell Lines

Abstract

The synthesis and characterization of new bis(bipyridine)ruthenium(II) ferrocenyl β‐diketonate complexes, [(bpy)2Ru(Fc‐acac)][PF6] (bpy=2,2′‐bipyridine; Fc‐acac=functionalized ferrocenyl β‐diketonate ligand) are reported. Alongside clinical platinum drugs, these bimetallic ruthenium‐iron complexes have been screened for their cytotoxicity against MIA PaCa‐2 (human pancreatic carcinoma), HCT116 p53+/+ (human colon carcinoma, p53‐wild type) and ARPE‐19 (human retinal pigment epithelial) cell lines. With the exception of one complex, the library exhibit nanomolar potency against cancerous cell lines, and their relative potencies are up to 40x, 400x and 72x more cytotoxic than cisplatin, carboplatin and oxaliplatin, respectively. Under hypoxic conditions, the complexes remain cytotoxic (sub‐micromolar range), highlighting their potential in targeting hypoxic tumor regions. The Comet assay was used to determine their ability to damage DNA, and results show dose dependent damage which correlates well with the cytotoxicity results. Their potential to treat bacterial and fungal strains has been determined, and highlight complexes have selective growth inhibition of up to 87–100 % against Staphylococcus aureus and Candida albicans.

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

“…82 However, studies on other Ru polypyridyl complexes with acac-based ferrocenyl β-diketonate ligands showed no selectivity toward cancerous HCT116 p53 +/+ cells over noncancerous ARPE-19 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.…”

“…Although 4−6 were also active in the triple-negative breast and prostate cancer cells, they were just as or more potent in the normal breast epithelial line, which is common for many anticancer drugs. 36 To understand the differential effects of 1−7 in cells, lipophilicities were determined (Table 2). Lipophilicity, measured as the partition coefficient between octanol and water (log P o/w ), has been previously correlated with the cytotoxicity of Ru(II) complexes.…”

“…Studies on DNA damage with these complexes revealed that they are able to cause DNA cleavage. 36 In this paper, we report the synthesis and biological characterization of Ru(II) polypyridyl complexes containing acac-based ligands. The spectral and electrochemical properties of these Ru−acac complexes were characterized.…”

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

“…It is considered that if the SI is greater than 2, then the more selective the compound is towards cancer cells. SI values less than or equal to 2 mean that the compound has only general toxicity [ 37 , 38 , 39 ]. The results show that the metallodendrimers are especially selective regarding A2780 cancer cells.…”

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

“…[6,7b,c] Given their potential biological properties, synthetic accessibility, and the ability to chelate metals, many coordination and organometallic complexes with k 2 -O,O'-ligands have been studied. Anticancer properties have been assessed using a range of different metals, including Pt(II), Ti(IV), V(IV), [1] Co(III), [9] Ir(III), [1,10] Os(II), Rh(III), [10] Ru(II) [10][11] and La(III). [12] Metal complexes made from similar k 2 -O,O'-chelating ligands, such as 2hydroxyacetophenones, [13] flavonols, [10,14] naphthoquinones, [10,15] and acylpyrazolones [7c] have also been investigated.…”